{"paper_id":"2956db5b-3a28-479b-9e41-2801db2e319a","body_text":"The Art of War: harnessing the epigenome against... | F1000Research <!-- --> <!-- --> <!-- This is commented out to fix display problems on mobile devices. We may use it again once we implement a responsive design that supports native device resolutions. --> \"use strict\";function _typeof(t){return(_typeof=\"function\"==typeof Symbol&&\"symbol\"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&\"function\"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?\"symbol\":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement(\"iframe\");r.style.cssText=\"display:none\",r.name=\"__tcfapiLocator\",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&\"boolean\"==typeof n[3]&&(e=n[3],\"function\"==typeof n[2]&&n[2](\"set\",!0)):\"ping\"===n[0]?\"function\"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:\"stub\"}):o.push(n)},n.addEventListener(\"message\",(function(t){var e=\"string\"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n=\"object\"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,\"*\")}),n.parameter)}),!1))};\"undefined\"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:[\"bam.nr-data.net\"]}}; ;NREUM.loader_config={accountID:\"438030\",trustKey:\"438030\",agentID:\"772317073\",licenseKey:\"97f8f67f26\",applicationID:\"772317073\"} ;NREUM.info={beacon:\"bam.nr-data.net\",errorBeacon:\"bam.nr-data.net\",licenseKey:\"97f8f67f26\",applicationID:\"772317073\",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{\"use strict\";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error(\"All info objects require an agent identifier!\");if(!a[e])throw new Error(\"Info for \".concat(e,\" was never set\"));return a[e]}function c(e,t){if(!e)throw new Error(\"All info objects require an agent identifier!\");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],\"info\")}var u=r(7056);const d=()=>{const e={blockSelector:\"[data-nr-block]\",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:\"*\",maskAllInputs:!0,get blockClass(){return\"nr-block\"},get ignoreClass(){return\"nr-ignore\"},get maskTextClass(){return\"nr-mask\"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=\",\".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error(\"All configuration objects require an agent identifier!\");if(!f[e])throw new Error(\"Configuration for \".concat(e,\" was never set\"));return f[e]}function h(e,t){if(!e)throw new Error(\"All configuration objects require an agent identifier!\");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],\"config\")}function g(e,t){if(!e)throw new Error(\"All configuration objects require an agent identifier!\");var r=l(e);if(r){for(var n=t.split(\".\"),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||\"object\"!=typeof e)return(0,n.Z)(\"Setting a Configurable requires an object as input\");if(!t||\"object\"!=typeof t)return(0,n.Z)(\"Setting a Configurable requires a model to set its initial properties\");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{\"object\"==typeof e[a]&&\"object\"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)(\"An error occurred while setting a property of a Configurable\",e)}return r}catch(e){(0,n.Z)(\"An error occured while setting a Configurable\",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n=\"1.236.0\",i=\"PROD\",o=\"CDN\"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n=\"undefined\"!=typeof window&&!!window.document,i=\"undefined\"!=typeof WorkerGlobalScope&&(\"undefined\"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||\"undefined\"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:\"undefined\"!=typeof WorkerGlobalScope&&(\"undefined\"!=typeof self&&self instanceof WorkerGlobalScope&&self||\"undefined\"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=\"\"+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&\"undefined\"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\\s](\\d+\\.\\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:\"\",ee:void 0};class o{constructor(e){try{if(\"object\"!=typeof e)return(0,n.Z)(\"shared context requires an object as input\");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)(\"An error occured while setting SharedContext\",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:\"\",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:\"feature\";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s=\"nr@context\";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&\"object\"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;f<d;f++)s[f].apply(a,r);var l=T()[c[e]];return l&&l.push([p,e,r,a]),a}}function b(e,t){n[e]=w(e).concat(t)}function y(e,t){var r=n[e];if(r)for(var i=0;i {r.d(t,{E:()=>n,p:()=>i});var n=r(2177).ee.get(\"handle\");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o=\"feature\"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener(\"test\",null,e),n._A.removeEventListener(\"test\",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i=\"xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx\";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split(\"\").map((e=>\"x\"===e?o(t,++r).toString(16):\"y\"===e?(3&o()|8).toString(16):e)).join(\"\")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n=\"NRBA\",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||\"\").indexOf(\"data:\"))return{protocol:\"data\"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement(\"a\"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split(\"://\");!o.port&&a[1]&&(o.port=a[1].split(\"/\")[0].split(\"@\").pop().split(\":\")[1]),o.port&&\"0\"!==o.port||(o.port=\"https\"===a[0]?\"443\":\"80\"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],\"/\"!==o.pathname.charAt(0)&&(o.pathname=\"/\"+o.pathname);var s=!t.protocol||\":\"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),\"/\"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){\"function\"==typeof console.warn&&(console.warn(\"New Relic: \".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&\"object\"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)(\"feat-\"+t,[],void 0,e,r):(0,i.p)(\"block-\"+t,[],void 0,e,r),(0,i.p)(\"rumresp-\"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)(\"feat-\"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)(\"rumresp-\"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if(\"object\"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit(\"internal-error\",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return\"undefined\"==typeof document||\"complete\"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)(\"load\",e,t)}function a(e){if(i())return e();(0,n.iz)(\"DOMContentLoaded\",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:\"bam.nr-data.net\",errorBeacon:\"bam.nr-data.net\"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)(\"visibilitychange\",(function(){if(t)return void(\"hidden\"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i=\"nr@original\";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n=\"\");var a,s,c,u=\"-\"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,\"fetch\",y),t.on(y+\"end\",(function(e,r){var n=this;if(r){var i=r.headers.get(\"content-length\");null!==i&&(n.rxSize=i),t.emit(y+\"done\",[null,r],n)}else t.emit(y+\"done\",[e],n)})),t}const O={},j=[\"pushState\",\"replaceState\"];function S(e){const t=function(e){return(e||n.ee).get(\"history\")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,\"-\")),t}var P=r(3239);const C={},R=[\"appendChild\",\"insertBefore\",\"replaceChild\"];function I(e){const t=function(e){return(e||n.ee).get(\"jsonp\")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\\.([^.]+)/,a=/^(\\w+)(\\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,\"dom-\"),t.on(\"dom-start\",(function(e){!function(e){if(!e||\"string\"!=typeof e.nodeName||\"script\"!==e.nodeName.toLowerCase())return;if(\"function\"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if(\"function\"!=typeof u.parent[u.key])return;var d={};function f(){t.emit(\"jsonp-end\",[],d),e.removeEventListener(\"load\",f,(0,P.m$)(!1)),e.removeEventListener(\"error\",l,(0,P.m$)(!1))}function l(){t.emit(\"jsonp-error\",[],d),t.emit(\"jsonp-end\",[],d),e.removeEventListener(\"load\",f,(0,P.m$)(!1)),e.removeEventListener(\"error\",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],\"cb-\",d),e.addEventListener(\"load\",f,(0,P.m$)(!1)),e.addEventListener(\"error\",l,(0,P.m$)(!1)),t.emit(\"new-jsonp\",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get(\"mutation\")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,\"fn-\")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get(\"promise\")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,\"executor-\",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,\"name\",{value:\"Promise\"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),[\"all\",\"race\"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a(\"all\"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit(\"propagate\",[null,!i],o,!1,!1),i=i||!e}}}})),[\"resolve\",\"reject\"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit(\"propagate\",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,[\"onreadystatechange\"],\"fn-\",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit(\"xhr-resolved\",[],e)),i.inPlace(e,f,\"fn-\",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,\"-xhr-\",E),r.on(\"send-xhr-start\",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on(\"open-xhr-start\",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on(\"fn-end\",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i=\"nr@seenError\"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i=\"sm\",o=\"cm\",a=\"storeSupportabilityMetrics\",s=\"storeEventMetrics\"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i=\"firstbyte\",o=\"domcontent\",a=\"windowload\"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i=\"bstResource\",o=\"resource\",a=\"-start\",s=\"-end\",c=\"fn\"+a,u=\"fn\"+s,d=\"pushState\"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=[\"click\",\"submit\",\"keypress\",\"keydown\",\"keyup\",\"change\"],a=999,s=\"fn-start\",c=\"fn-end\",u=\"cb-start\",d=\"api-ixn-\",f=\"remaining\",l=\"interaction\",h=\"spaNode\",g=\"jsonpNode\",p=\"fetch-start\",m=\"fetch-done\",v=\"fetch-body-\",b=\"jsonp-end\",y=n.Yu.ST,w=\"-start\",x=\"-end\",A=\"-body\",E=\"cb\"+x,T=\"jsTime\",_=\"fetch\"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();[\"setErrorHandler\",\"finished\",\"addToTrace\",\"inlineHit\",\"addRelease\",\"addPageAction\",\"setCurrentRouteName\",\"setPageViewName\",\"setCustomAttribute\",\"interaction\",\"noticeError\",\"setUserId\"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,\"api\");const h={};var g=a.ee.get(e),p=g.get(\"tracer\"),m=\"api-\",v=m+\"ixn-\";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?\"session\":void 0)(t,r)}function y(){}[\"setErrorHandler\",\"finished\",\"addToTrace\",\"inlineHit\",\"addRelease\"].forEach((e=>h[e]=x(m,e,!0,\"api\"))),h.addPageAction=x(m,\"addPageAction\",!0,n.D.pageAction),h.setCurrentRouteName=x(m,\"routeName\",!0,n.D.spa),h.setPageViewName=function(t,r){if(\"string\"==typeof t)return\"/\"!==t.charAt(0)&&(t=\"/\"+t),(0,i.OP)(e).customTransaction=(r||\"http://custom.transaction\")+t,x(m,\"setPageViewName\",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if(\"string\"==typeof e){if([\"string\",\"number\"].includes(typeof t)||null===t)return b(e,t,\"setCustomAttribute\",r);(0,f.Z)(\"Failed to execute setCustomAttribute.\\nNon-null value must be a string or number type, but a type of was provided.\"))}else(0,f.Z)(\"Failed to execute setCustomAttribute.\\nName must be a string type, but a type of was provided.\"))},h.setUserId=function(e){if(\"string\"==typeof e||null===e)return b(\"enduser.id\",e,\"setUserId\",!0);(0,f.Z)(\"Failed to execute setUserId.\\nNon-null value must be a string type, but a type of was provided.\"))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a=\"function\"==typeof t;return(0,o.p)(v+\"tracer\",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?\"\":\"no-\")+\"fn-start\",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit(\"fn-err\",[arguments,this,\"string\"==typeof e?new Error(e):e],r),e}finally{p.emit(\"fn-end\",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,[\"API/\"+t+\"/called\"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,\"api\")})).catch((()=>(0,f.Z)(\"Downloading runtime APIs failed...\")))}return[\"actionText\",\"setName\",\"setAttribute\",\"save\",\"ignore\",\"onEnd\",\"getContext\",\"end\",\"get\"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){\"string\"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,[\"API/noticeError/called\"],void 0,n.D.metrics,g),(0,o.p)(\"err\",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,\"api\"),(0,h.Qy)(e,A,\"exposed\"),(0,h.EZ)(\"activatedFeatures\",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:\"ajax\",jserrors:\"jserrors\",metrics:\"metrics\",pageAction:\"page_action\",pageViewEvent:\"page_view_event\",pageViewTiming:\"page_view_timing\",sessionReplay:\"session_replay\",sessionTrace:\"session_trace\",spa:\"spa\"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:\"page_action-aggregate\",147:\"metrics-aggregate\",242:\"session-manager\",317:\"jserrors-aggregate\",348:\"page_view_timing-aggregate\",412:\"lazy-feature-loader\",439:\"async-api\",538:\"recorder\",590:\"session_replay-aggregate\",675:\"compressor\",733:\"session_trace-aggregate\",786:\"page_view_event-aggregate\",873:\"spa-aggregate\",898:\"ajax-aggregate\"}[e]||e)+\".\"+{78:\"ac76d497\",147:\"3dc53903\",148:\"1a20d5fe\",242:\"2a64278a\",317:\"49e41428\",348:\"bd6de33a\",412:\"2f55ce66\",439:\"30bd804e\",538:\"1b18459f\",590:\"cf0efb30\",675:\"ae9f91a8\",733:\"83105561\",786:\"06482edd\",860:\"03a8b7a5\",873:\"e6b09d52\",898:\"998ef92b\"}[e]+\"-1.236.0.min.js\"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t=\"NRBA:\",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName(\"script\"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:\"timeout\",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{\"undefined\"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:\"Module\"}),Object.defineProperty(e,\"__esModule\",{value:!0})},i.j=364,i.p=\"https://js-agent.newrelic.com/\",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&(\"load\"===r.type?\"missing\":r.type),a=r&&r.target&&r.target.src;s.message=\"Loading chunk \"+t+\" failed.\\n(\"+o+\": \"+a+\")\",s.name=\"ChunkLoadError\",s.type=o,s.request=a,n[1](s)}}),\"chunk-\"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,\"\".concat(e,\".enabled\"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,\"privacy.cookies_enabled\");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)(\"A problem occurred when starting up session manager. This page will not start or extend any session.\",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,\"aggregate\");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)(\"Downloading and initializing \".concat(this.featureName,\" failed...\"),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,\"session_trace.enabled\")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),(\"undefined\"==typeof PerformanceNavigationTiming||c.Tt)&&\"undefined\"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)(\"timing\",[\"load\",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if(\"count\"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r=\"\",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean(\"hidden\"===document.visibilityState),(0,N.N)((()=>(0,s.p)(\"docHidden\",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)(\"pagehide\",(()=>(0,s.p)(\"winPagehide\",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem(\"__nr_flags\").split(\",\"),console&&\"function\"==typeof console.log&&(L.console=!0,-1!==R.indexOf(\"dev\")&&(L.dev=!0),-1!==R.indexOf(\"nr_dev\")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on(\"internal-error\",(function(e){z(e.stack)})),L.dev&&H.ee.on(\"fn-err\",(function(e,t,r){z(r.stack)})),L.dev&&(z(\"NR AGENT IN DEVELOPMENT MODE\"),z(\"flags: \"+(0,b.D)(L,(function(e,t){return e})).join(\", \")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on(\"fn-start\",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on(\"fn-err\",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)(\"err\",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on(\"fn-end\",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on(\"internal-error\",(function(t){(0,s.p)(\"ierr\",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener(\"unhandledrejection\",(t=>{const r=function(e){let t=\"Unhandled Promise Rejection: \";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)(\"err\",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){\"function\"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)(\"err\",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)(\"ierr\",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||\"Uncaught error with no additional information\",this.sourceURL=t,this.line=r}let U=1;const q=\"nr@id\";function G(e){const t=typeof e;return!e||\"object\"!==t&&\"function\"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if(\"string\"==typeof e&&e.length)return e.length;if(\"object\"==typeof e){if(\"undefined\"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if(\"undefined\"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!(\"undefined\"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||\"\").toString()||null,i=(r.agentID||\"\").toString()||null,o=(r.trustKey||\"\").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return\"00-\"+t+\"-\"+e+\"-01\"}generateTraceContextStateHeader(e,t,r,n,i){return i+\"@nr=0-1-\"+r+\"-\"+n+\"-\"+e+\"----\"+t}generateTraceHeader(e,t,r,n,i,o){if(!(\"function\"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:\"Browser\",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,\"distributed_tracing\")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener(\"load\",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener(\"progress\",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader(\"X-NewRelic-ID\",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader(\"newrelic\",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader(\"traceparent\",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader(\"tracestate\",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{\"abort\"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),(\"load\"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||\"function\"!=typeof t.onload)&&\"function\"==typeof o.end)&&o.end(t)}catch(e){try{n.emit(\"internal-error\",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set(\"newrelic\",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set(\"traceparent\",t.traceContextParentHeader),t.traceContextStateHeader&&e.set(\"tracestate\",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;\"string\"==typeof i?r=i:\"object\"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&\"object\"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(\"\"+(i&&i instanceof Y&&i.method||n.method||\"GET\")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,\"string\"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i(\"xhr\",[this.params,o,this.startTime,this.endTime,\"fetch\"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||\"agent\")),this.start()):(0,l.Z)(\"Failed to initial the agent. Could not determine the runtime environment.\")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t=\"features\";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)(\"\".concat(t.featureName,\" is enabled but one or more dependent features has been disabled (\").concat((0,D.P)(n),\"). This may cause unintended consequences or missing data...\")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)(\"Failed to initialize all enabled instrument classes (agent aborted) -\",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)(\"bst\",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)(\"bstHist\",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get(\"tracer\"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get(\"events\"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit(\"newURL\",[\"\"+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,\"xhr-resolved\"],this.featureName),f.buffer([ve],this.featureName),u.buffer([\"setTimeout\"+le,\"clearTimeout\"+fe,ve],this.featureName),d.buffer([ve,\"new-xhr\",\"send-xhr\"+fe],this.featureName),l.buffer([me+fe,me+\"-done\",me+he+fe,me+he+le],this.featureName),h.buffer([\"newURL\"],this.featureName),g.buffer([ve],this.featureName),s.buffer([\"propagate\",be,ge,\"executor-err\",\"resolve\"+fe],this.featureName),o.buffer([ve,\"no-\"+ve],this.featureName),a.buffer([\"new-jsonp\",\"cb-start\",\"jsonp-error\",\"jsonp-end\"],this.featureName),y(l,me+fe),y(l,me+\"-done\"),y(a,\"new-jsonp\"),y(a,\"jsonp-end\"),y(a,\"cb-start\"),h.on(\"pushState-end\",m),h.on(\"replaceState-end\",m),window.addEventListener(\"hashchange\",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener(\"load\",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener(\"popstate\",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:\"spa\"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is \"complete\" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event \"completion\" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', \"PixelInitialized\", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { \"@context\": \"https://schema.org\", \"@type\": \"ScholarlyArticle\", \"mainEntityOfPage\": { \"@type\": \"WebPage\", \"@id\": \"https://f1000research.com/articles/7-141\" }, \"headline\": \"The Art of War: harnessing the epigenome against cancer\", \"datePublished\": \"2018-02-02T09:00:05\", \"dateModified\": \"2018-02-02T09:00:05\", \"author\": [ { \"@type\": \"Person\", \"name\": \"Jonathan Nye\" }, { \"@type\": \"Person\", \"name\": \"Daniël P. Melters\" }, { \"@type\": \"Person\", \"name\": \"Yamini Dalal\" } ], \"publisher\": { \"@type\": \"Organization\", \"name\": \"F1000Research\", \"logo\": { \"@type\": \"ImageObject\", \"url\": \"https://f1000research.com/img/AMP/F1000Research_image.png\", \"height\": 480, \"width\": 60 } }, \"image\": { \"@type\": \"ImageObject\", \"url\": \"https://f1000research.com/img/AMP/F1000Research_image.png\", \"height\": 1200, \"width\": 150 }, \"description\": \"Histone chaperones are indispensable regulators of chromatin structure and function. Recent work has shown that they are frequently mis-regulated in cancer, which can have profound consequences on tumor growth and survival. Here, we focus on chaperones for the essential H3 histone variants H3.3 and CENP-A, specifically HIRA, DAXX/ATRX, DEK, and HJURP. This review summarizes recent studies elucidating their roles in regulating chromatin and discusses how cancer-specific chromatin interactions can be exploited to target cancer cells.\" } { \"@context\": \"http://schema.org\", \"@type\": \"BreadcrumbList\", \"itemListElement\": [ { \"@type\": \"ListItem\", \"position\": \"1\", \"item\": { \"@id\": \"https://f1000research.com/\", \"name\": \"Home\" } }, { \"@type\": \"ListItem\", \"position\": \"2\", \"item\": { \"@id\": \"https://f1000research.com/browse/articles\", \"name\": \"Browse\" } }, { \"@type\": \"ListItem\", \"position\": \"3\", \"item\": { \"@id\": \"https://f1000research.com/articles/7-141\", \"name\": \"The Art of War: harnessing the epigenome against cancer\" } } ] } Home Browse The Art of War: harnessing the epigenome against cancer ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Nye J, Melters DP and Dalal Y. The Art of War: harnessing the epigenome against cancer [version 1; peer review: 4 approved] . F1000Research 2018, 7 (F1000 Faculty Rev):141 ( https://doi.org/10.12688/f1000research.12833.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review The Art of War: harnessing the epigenome against cancer [version 1; peer review: 4 approved] Jonathan Nye 1 , Daniël P. Melters 1 , Yamini Dalal https://orcid.org/0000-0002-7655-6182 1 Jonathan Nye 1 , Daniël P. Melters 1 , Yamini Dalal https://orcid.org/0000-0002-7655-6182 1 PUBLISHED 02 Feb 2018 Author details Author details 1 Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Jonathan Nye Roles: Conceptualization, Writing – Original Draft Preparation Daniël P. Melters Roles: Writing – Original Draft Preparation Yamini Dalal Roles: Conceptualization, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Histone chaperones are indispensable regulators of chromatin structure and function. Recent work has shown that they are frequently mis-regulated in cancer, which can have profound consequences on tumor growth and survival. Here, we focus on chaperones for the essential H3 histone variants H3.3 and CENP-A, specifically HIRA, DAXX/ATRX, DEK, and HJURP. This review summarizes recent studies elucidating their roles in regulating chromatin and discusses how cancer-specific chromatin interactions can be exploited to target cancer cells. READ ALL READ LESS Keywords Epigenome, Histone chaperones, chromatin, cancer, tumor growth Corresponding Author(s) Yamini Dalal ( [email protected] ) Close Corresponding author: Yamini Dalal Competing interests: No competing interests were disclosed. Grant information: All authors were supported by the Intramural Research Program of the Center for Cancer Research at the National Cancer Institute The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2018 Nye J et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. How to cite: Nye J, Melters DP and Dalal Y. The Art of War: harnessing the epigenome against cancer [version 1; peer review: 4 approved] . F1000Research 2018, 7 (F1000 Faculty Rev):141 ( https://doi.org/10.12688/f1000research.12833.1 ) First published: 02 Feb 2018, 7 (F1000 Faculty Rev):141 ( https://doi.org/10.12688/f1000research.12833.1 ) Latest published: 02 Feb 2018, 7 (F1000 Faculty Rev):141 ( https://doi.org/10.12688/f1000research.12833.1 ) Introduction Histones are a highly conserved family of proteins that facilitate the compaction of DNA by wrapping it around an octamer containing two copies each of the canonical histones H2A, H2B, H3, and H4. These canonical forms comprise the large majority of all histones bound to DNA and are responsible for the regulation of a variety of cellular processes including replication, transcription, and DNA repair. In addition, several histone variants have evolved to allow for additional levels of regulation. These variants can differ from their canonical counterparts in sequence, structure, and the timing of their incorporation. Canonical histone assembly is typically coupled to DNA replication at S-phase, whereas the assembly of histone variants is replication independent and spans all phases of the cell cycle 1 . Human histone variants have been identified for all canonical histones except for H4. The canonical histone H3 has six variants including H3.3, CENP-A, H3.1T, H3.5, H3.X, and H3.Y 2 . This diversity allows for variants that specialize in a wide variety of different functions, including the regulation of transcription, chromosome segregation, and telomere function. Interestingly, the two most abundantly expressed and essential H3 variants differ not only in function but also in how much they have diverged from the canonical form. For example, the H3 variant H3.3 differs by five amino acids and shares 96.3% amino acid sequence similarity with its canonical counterpart H3.1; in contrast, CENP-A exhibits only 45.1% similarity with H3.1 2 . Furthermore, while their assembly is replication-independent, they localize to distinct regions of the genome: CENP-A is normally found predominantly at the centromere, whereas H3.3 localizes to heterochromatin, telomeres, enhancers, and genic areas of high nucleosome turnover ( Figure 1 ). Figure 1. Histone chaperones allow for assembly at specific genomic regions. The histone variant H3.3 relies on three specific chaperones for deposition at specific locations in the genome. The chaperones DEK, DAXX/ATRX, and HIRA have been shown to prefer distinct sites for H3.3 assembly. Furthermore, they have been found to be mis-regulated in many cancer types, as shown. The centromeric histone variant CENP-A normally associates with a single chaperone called HJURP. However, changes in the amount of CENP-A compared to its chaperone can allow for deposition throughout chromosome arms by the H3.3 chaperone DAXX. The precise localization and assembly of these histones into chromatin is thought to be achieved through their interaction with histone variant specific chaperones by mechanisms not yet entirely elucidated. In addition, some chaperones are found to be closely associated with ATP-dependent chromatin remodelers. For example, proper H3.3 assembly and localization relies on the histone chaperone DAXX in complex with the SWI/SNF-like chromatin remodeler ATRX. Interestingly, H3.3 can associate with multiple chaperones, including HIRA and DEK, in addition to DAXX/ATRX. In contrast, human CENP-A normally associates with a single centromeric chaperone called HJURP. Intriguingly, while it has long been assumed that histone chaperones are mere carriers of histones, recent advances, including patient tumor sequencing data, have shown that these critical chaperones may play an unanticipated role in disease progression. Here, we review recent literature on this subject and ask how changes in variant chaperones can influence the histone variant chromatin landscape in the epigenome and thereby impact human health. HIRA and senescence The histone cell cycle regulator (HIRA) protein has been found to be a chaperone facilitating the assembly of the histone variant H3.3 into chromatin in a replication-independent manner 3 . It is at the center of a complex of proteins, conserved from yeast to humans, referred to as the HUCA complex that consists primarily of HIRA, UBN1, CABIN1, and transiently includes Asf1 4 . The UBN1 subunit imparts specificity to the complex by preferentially binding to H3.3/H4 over H3.1/H4, thereby enabling this dimer’s assembly into chromatin 5 . Unlike other H3 variants like CENP-A, H3.3 normally associates with multiple chaperones and each complex appears to be responsible for its localization to specific places in the genome. For example, HIRA is necessary for H3.3 deposition at gene regulatory elements, gene bodies, and sites of DNA damage 6 , 7 . Targeting of the HIRA complex is thought to be achieved through its interaction with a number of different proteins including transcription factors, chromatin remodelers, and the single-stranded DNA (ssDNA)-binding protein RPA 6 , 8 . However, the precise mechanism by which this chaperone hones in on the correct regions of the genome has not been clearly elucidated. One possibility is that HIRA recruitment to gene regulatory regions requires the presence of R-loops. These RNA–DNA hybrid structures attract RPA owing to the presence of exposed ssDNA, which then recruits the HIRA complex and leads to H3.3 assembly at these sites. From these studies, it is clear that the HIRA complex is an important regulator of H3.3 deposition, but HIRA’s role in human health is still unclear. This is particularly intriguing because human HIRA was originally identified through the study of DiGeorge syndrome patients, who commonly have heart and brain abnormalities, arising from a deletion of the q11 cytogenetic band of chromosome 22, which contains the HIRA gene 9 , 10 . Despite intense study, it is still unclear as to whether HIRA is responsible for these defects or if it is a result of the deletion of multiple genes. More recently, HIRA has been shown to have a clear role in establishing and maintaining senescence. Indeed, early studies discovered that HIRA and Asf1 are necessary for the formation of senescence-associated heterochromatic foci, which, in turn, are thought to be essential to shut down genes involved in cell cycle progression 11 . Furthermore, the overexpression of HIRA and Asf1 is sufficient to induce senescence. In addition, post-translational modifications of HIRA have been identified and were shown to be necessary for its function. Consistent with HIRA’s proposed role, the expression of a non-modifiable mutant led to defects in senescence 12 . Multiple mechanisms have been proposed to explain the role of HIRA in the establishment of senescence. One provocative possibility involves a cleaved H3.3 protein lacking the first 21 amino acids. HIRA-mediated assembly of this cleaved protein has been shown to be sufficient to induce senescence and results in the repression of cell cycle regulators 13 . Other work has reported that HIRA is necessary for replication-independent deposition of H3.3 in senescent cells and for maintaining the H4K16ac histone mark at gene promoters 14 , 15 . Furthermore, the same study found that HIRA was required to suppress oncogene-induced neoplasia in a mouse model. This work highlights the importance of this H3.3 chaperone in fine tuning the chromatin environment to allow cells to permanently exit the cell cycle and preventing uncontrolled cell growth. As discussed in the next section, many questions remain unanswered: for instance, how is HIRA function affected by changes in levels of another H3.3 chaperone, DAXX, commonly observed in tumors? For example, can HIRA bind to other H3 variants as has been observed with DAXX? Furthermore, in Arabidopsis, H3.3 and DNA methylation are inversely related and H3.3 knockdown alters the DNA methylation profile 16 , 17 . Moreover, it has been proposed that H3.3 prevents the recruitment of the linker histone H1 18 . These findings beg the following questions: can global changes in DNA methylation, coupled to widespread mis-regulation of linker histone H1 isoforms, both commonly associated with cancer, alter H3.3 deposition? Or, conversely, does gain or loss of H3.3 at a specific locus alter its DNA methylation profile? Both of these fundamental questions need to be addressed in future studies. H3.3 deposition by DAXX/ATRX in cancer The histone chaperone DAXX, or death domain-associated protein, was originally named for its association with the Fas receptor, wherein it was thought to induce apoptosis by activating the JNK pathway 19 . However, further work identified it as a bona fide H3.3 chaperone that forms a complex with the SWI/SNF-like chromatin remodeler ATRX 20 – 22 . Like other H3.3 chaperones, ATRX/DAXX targets H3.3 to very specific regions of the genome in a replication-independent manner, specifically, to telomeres, pericentric heterochromatin, and other repetitive elements 23 – 25 . Both ATRX and DAXX seem to be equally important in this process, with DAXX providing the H3.3 binding specificity and chaperone activity while ATRX targets the complex in part through binding to modified histones like H3K9me3 and also stretches of G-rich repeats with a unique secondary DNA structure called a G-quadruplex 26 – 30 . Moreover, proper functioning of this complex is critical, since mutations in both of these proteins have been strongly linked to cancer and other diseases ( Figure 2B , Table 1 ). Figure 2. Mutations in H3 variant chaperones occur in many cancer types. A . Percentage of cases affected by HIRA mutations in multiple cancer types obtained from The Cancer Genome Atlas (TCGA) analysis. Numbers listed above each bar represent total number of cases analyzed. TCGA cancer types listed in order from left to right include uterine corpus endometrial carcinoma (UCEC), skin cutaneous melanoma (SKCM), colon adenocarcinoma (COAD), stomach adenocarcinoma (STAD), urothelial bladder carcinoma (BLCA), head–neck squamous cell carcinoma (HNSC), lung squamous cell carcinoma (LUSC), glioblastoma multiforme (GBM), rectum adenocarcinoma (READ), and cholangiocarcinoma (CHOL). Locations of mutations within the HIRA protein. HIRA protein domains include a WD-40 repeat-containing domain, the B-domain (B) necessary for binding to Asf1, and the conserved Hir domain. B . DAXX mutations as above. TCGA cancer types listed in order from left to right include UCEC, SKCM, adrenocortical carcinoma (ACC), STAD, COAD, LUSC, BLCA, lung adenocarcinoma (LUAD), GBM, and READ. DAXX protein domains include the four-helix bundle (4HB) necessary for ATRX binding, a histone-binding domain, an acidic domain, and the Ser/Pro/Thr-rich region. C . DEK oncogene mutations listed as above. TCGA cancer types listed in order from left to right include UCEC, diffuse large B-cell lymphoma (DLBC), STAD, COAD, cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), BLCA, pancreatic adenocarcinoma (PAAD), SKCM, GBM, and ovarian cancer (OV). DEK protein domains shown include a DNA-binding domain, the scaffold attachment factor-box (SAF), and a DNA-binding and multimerization domain. D . HJURP mutations listed as above. TCGA cancer types listed in order from left to right include UCEC, SKCM, READ, STAD, COAD, CESC, OV, LUAD, uterine carcinosarcoma (UCS), and BLCA. HJURP protein domains include the SCM3 domain, the conserved domain (CD), the HJURP C-terminal domain (HCTD) responsible for centromere targeting, and the dimerization domain. Table 1. Expression changes of histone variant chaperones in cancer. ALT, alternative lengthening of telomeres; GBM, gliobastoma multiforme. Histone Variant Chaperone/Chromatin Remodeler Cancer Expression Level Functional Consequences Refs H3.3 HIRA ? Decreased levels prevent senescence and increase oncogene-induced neoplasia in mouse model 14 DAXX Increased Promotes tumor growth in mouse prostate cancer model Increased expression of oncogenes in GBM cells lacking PTEN Promotes mis-localization of CENP-A, leading to chromosomal instability Promotes proliferation and resistance to anticancer treatments 39 38 40 – 42 43 Decreased Potentiates Slug-driven lung cancer metastasis 37 ATRX Decreased Activation of ALT pathway 36 DEK Increased Upregulates anti-apoptotic factors Fusion protein dominant negative for DEK function Increased colony formation and tumorigenesis 44 45 – 50 51 CENP-A HJURP Increased ? 52 – 60 Decreased Chromosomal instability 61 , 62 ATRX was first discovered by identifying mutations in patients with an inherited disorder, ATRX syndrome, which resulted in a wide array of developmental defects 31 . Since then, mutations in both ATRX and DAXX have been found in a variety of different tumor types and seem to be especially prevalent in tumors associated with the central nervous system 32 – 35 . For example, in pediatric glioblastoma multiforme (GBM), 31% of patients have mutations in either ATRX or DAXX 36 . It is unclear how these mutations are driving cancer in young patients, but it is likely that ATRX and DAXX deficiencies have adverse effects on chromatin structure that may contribute to the development of cancer. As has been noted in patient tumors, ATRX/DAXX deficiency is commonly associated with alternative lengthening of telomeres (ALT) pathway activation, in which telomere length is maintained in a telomerase-independent manner, allowing cell growth to continue on uncontrolled 37 . Moreover, DAXX has also been shown to suppress lung cancer metastasis driven by the transcription factor Slug, directly binding to it, sequestering it, and preventing its association with DNA. Consequently, low DAXX expression levels correlated with lower overall survival in lung cancer patients with Slug expression 38 . While these studies conclude that DAXX activity may serve a cancer-protective function, recent work has shown, conversely, that the presence of DAXX in some cases may enhance tumor growth as well as generate resistance to treatment. For example, in GBM cells lacking the tumor suppressor PTEN, there is a DAXX-dependent increase in the expression of oncogenes, and inhibition of DAXX in this context can suppress tumor growth 39 . DAXX has also been found to promote tumor growth in a mouse xenograft model of prostate cancer 40 . Furthermore, ONCOMINE meta-analysis revealed that overexpression of DAXX is common in prostate cancer patients and correlates with lower survival rates, suggesting that, in certain cases, DAXX may present itself as a viable therapeutic target. One possibility is that chaperones might, in the cancer background, bind inappropriately to the wrong histone variant. Indeed, recent studies have shown that DAXX can bind to the centromeric histone variant CENP-A, which is naturally overexpressed in colorectal cancer cells. Indeed, both DAXX and ATRX are present at severalfold excess in these cells 41 . These data suggest that serendipitous overexpression of chaperones alongside non-target histone variants might promote their association and drives mis-localization. Interestingly, this mis-localization has been shown to lead to genomic instability and also greater resistance to anticancer treatments 42 , 43 . These findings may provide a mechanistic explanation for earlier data showing that DAXX appears to promote proliferation and chemoresistance in ovarian cancer cells 63 . From these studies, it is clear that the roles of DAXX and ATRX in cancer are complex and dependent on many factors, including the accompanying mutations, the tumor type, and alterations in histone variant expression. In the future, it will be important to understand exactly how changes in DAXX expression can drive cancer progression. It is likely that cells rely on a delicate balance between different chaperones. It will be interesting to test whether the phenotypes observed when DAXX is overexpressed are due to a titration of H3.3 away from HIRA, resulting in mis-regulation of gene regulatory elements, or defects in senescence, both thought to be controlled by that chaperone. If so, this would support a “chaperone competition” model, in which changes in chaperone expression lead to widespread changes in localization of their target histone variants and binding of chaperones to non-cognate partners, thereby potentially driving tumorigenesis. The proto-oncogene DEK In addition to HIRA and DAXX, another H3.3 chaperone exists, namely the proto-oncogene DEK 64 . DEK has been implicated in a wide variety of cellular processes including transcription, replication, and DNA repair 65 . Interestingly, DEK also has the unique ability to bind preferentially to four-way junction DNA and induce positive supercoiling 66 , 67 . In its role as an H3.3 chaperone, it has been shown to play a critical role in regulating the deposition of H3.3 by HIRA and ATRX/DAXX 68 . Depletion of DEK in embryonic stem cells leads to the promiscuous incorporation of H3.3 throughout chromosome arms and pericentric heterochromatin by HIRA and DAXX. However, H3.3 is lost from telomeric chromatin and results in telomere dysfunction. Thus, DEK seems to behave as a gatekeeper, maintaining a balance between soluble and chromatin-bound H3.3 by modulating access to H3.3 by different chaperones. As with the other chaperones, DEK overexpression can be found in many cancer types and correlates with increased proliferation and tumorigenesis ( Table 1 ) 42 , 44 , 69 – 74 . DEK may promote tumorigenesis in multiple ways. First, it has been shown to prevent apoptosis by upregulating anti-apoptotic factors 45 . Consequently, reducing DEK levels led to increased apoptosis and susceptibility to genotoxic agents in melanomas. Second, in acute myeloid leukemia, DEK has been reported to be the target of translocations that generate a fusion protein with NUP214 46 – 50 . Precisely how this contributes to tumorigenesis is unclear; however, this fusion protein has been shown to interact with wild-type DEK and also inhibits chaperone activity 64 . Third, DEK overexpression has been shown to inhibit senescence 63 . Indeed, DEK levels are reduced upon replicative senescence, and overexpression of the protein leads to prolonged lifespan. Consequently, DEK-knockout mice develop fewer tumors in a chemical carcinogenesis model, while overexpression leads to increased colony formation and tumorigenesis 75 . Since DEK is involved in so many different pathways, it will not be trivial to pin down exactly how, or whether, its overexpression promotes tumorigenesis via histone variant assembly pathways. One possibility involves its regulation of H3.3 assembly by HIRA and DAXX. Normally, DEK seems to function to counteract the assembly of H3.3 by these two complexes by maintaining the soluble pre-nucleosomal H3.3 pool 68 . Thus, overexpression may prevent the proper assembly of this important histone variant by sequestering away H3.3 from HIRA or from DAXX. Indeed, it has been shown that depletion of HIRA leads to defects in senescence 11 – 14 , which has also been shown in cases of DEK overexpression 51 . The centromeric chaperone HJURP The centromere-specific histone H3 variant CENP-A/CENH3 is the epigenetic mark that specifies the site for kinetochore assembly during mitosis 76 . This allows for proper microtubule attachment to the chromosome and facilitates proper segregation of sister chromatids during anaphase. Like the H3.3 histone variant, CENP-A deposition occurs in a replication-independent manner. In human cells, the histone chaperone HJURP is responsible for its deposition during late mitosis/early G1 61 , 77 – 78 . HJURP localization and licensing is tightly linked to cell cycle progression and requires phosphorylation by CDK/cyclin A 79 , 80 . Both in the soluble preassembly complex and on chromatin, HJURP forms a homodimer 81 . Chromatin-bound HJURP is lost from centromeric chromatin by late G1/early S phase 52 , while a trace amount of it appears to return after replication, which may ensure that CENP-A can be deposited once and only once per cell cycle. Like most other histone chaperones, the overexpression of HJURP has been observed in various cancers 53 – 60 . In particular, breast, liver, and prostate cancer mis-regulate 14 centromere and kinetochore genes, including HJURP 82 ; this combinatorial mis-regulation has been proposed as a prognostic and predictive marker. These data also provide tantalizing functional links between cancer progression and mis-regulation of centromere chromatin because half of the 14 mis-regulated genes were found to be involved in the directed assembly of CENP-A nucleosomes. Interestingly, recent work has shown that the tumor suppressor p53 binds to elements in the promoters of CENP-A and HJURP and serves to repress the expression of these genes. Thus, loss of p53, a common phenomenon in cancer, can result in the overexpression of HJURP and CENP-A 62 . Indeed, in colon cancer cells with a mutated p53 gene, a DNase I hotspot maps to the CENP-A promoter, suggesting enhanced transcription of this gene, and correlates with increased RNA and protein levels of CENP-A 41 . This might explain why various types of tumors overexpress HJURP and CENP-A. In addition, a SNP located in the HJURP gene was found to be associated with increased risk for hepatocellular carcinoma among a Chinese population that were infected with hepatitis B virus 83 . This correlated with a decrease in expression of HJURP at the mRNA and protein level. These observations raise several questions. First, can changes in HJURP expression observed in cancer result in ectopic deposition of CENP-A? Indeed, in various cancers, ectopic CENP-A has been observed 41 , 84 , and the overexpression of CENP-A has been shown to be sufficient for ectopic localization 42 , 43 . Furthermore, this ectopic localization of CENP-A can result in chromosome instability. As noted above, CENP-A is deposited ectopically not by HJURP but by the H3.3 chaperone DAXX. This would suggest that when HJURP is limiting, CENP-A can bind promiscuously to other chaperones, allowing for ectopic localization 85 . In addition, ectopic CENP-A nucleosomes can form highly stable heterotypic CENP-A/H3.3 nucleosomes 41 , 42 , 86 . The origin, and consequences, of these heterotypic hybrid nucleosomes in vivo is a focus of intense studies. One possibility is that CENP-A is able to associate directly with DAXX but requires HJURP as an intermediate chaperone. Another possibility is that upon HJURP overexpression, DAXX and HJURP can form a heterodimer analogous to the HJURP homodimer, leading to the formation of these heterotypic nucleosomes 81 . Finally, in high-turnover regions, H3.3 nucleosomes are thought to ‘split’ in half during transit of RNA polymerases 87 – 89 , providing a tantalizing means for invasion of an existing H3.3 nucleosome by a dimer of CENP-A/H4. Second, can mutations in CENP-A’s protein sequence, or in the gain or loss of specific post-translational modifications, alter its affinity for HJURP in cancer? Recently, a modification of CENP-A through acetylation and ubiquitination of lysine 124 as well as phosphorylation of serine 68 was discovered 52 , 90 – 93 . Interestingly, ubiquitination of K124 and phosphorylation of S68 seem to play antagonistic roles, the first being necessary for HJURP binding and the latter inhibiting it, resulting in enhanced ectopic localization 93 , 94 . In addition, recent work has shown that when the tumor suppressor Fbw7 is lost, CENP-A S18 becomes hyper-phosphorylated, leading to chromosomal instability and tumor progression as a result of reduced CENP-A at centromeres 95 . It is clear from this work that the proper localization and function of CENP-A relies on modifications that either enhance or reduce its affinity for the chaperone HJURP. However, it is also likely that cancer cells exploit these pathways to promote tumor growth. In the future, it will be interesting to investigate whether this occurs for other H3 variants as well. For example, pre-assembly H3.3/H4 heterodimers have also been shown to be modified, but it is unclear whether these modifications are altered in tumors 96 , 97 . Conclusion A major problem when trying to identify specific mechanisms that promote tumorigenesis is that even seemingly subtle changes, such as point mutations in a chaperone ( Figure 2 ), can dramatically alter the epigenetic landscape of a tumor 36 . Therefore, in the battle against cancer, the enemy has an apparent advantage. Indeed, in this regard, cancer cells appear to have mastered the maxim, “be extremely subtle, even to the point of formlessness... thereby you can be the director of the opponent's fate” ( Sun Tzu , The Art of War ). The crucial question is whether the chaperone–histone mis-interactions listed above, driven by mutation, mis-expression, or mis-regulation, can serve as therapeutic targets in the treatment of disease 98 . What makes such interactions an attractive target is precisely that they do not exist in normal cells. Thus, there are likely a small set of critical interactions that might be meaningful to exploit. Consequently, it will be informative to test whether identifying and blocking cancer-specific interactions between histone variants and chaperones, such as DAXX binding to CENP-A, or between chaperones and chromatin regulatory complexes can serve as a potent method to singularly attack cancer-specific networks while sparing normal cells. In this quest, using advanced techniques such as molecular docking, computational modeling, sophisticated machine-learning algorithms to query mutated protein interactomes, and focused small molecule design to identify and disrupt local affinities in protein–protein or DNA–protein interactions presents exciting and promising avenues of research. Thus, in our battle against disease, we note another maxim that promises hope: \"in the midst of chaos, there is also opportunity” (Sun Tzu, The Art of War ). Competing interests The authors declare that they have no competing interests. Grant information All authors were supported by the Intramural Research Program of the Center for Cancer Research at the National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript . Faculty Opinions recommended References 1. Szenker E, Ray-Gallet D, Almouzni G: The double face of the histone variant H3.3. Cell Res. 2011; 21 (3): 421–34. PubMed Abstract | Publisher Full Text | Free Full Text 2. Buschbeck M, Hake SB: Variants of core histones and their roles in cell fate decisions, development and cancer. Nat Rev Mol Cell Biol. 2017; 18 (5): 299–314. PubMed Abstract | Publisher Full Text 3. Tagami H, Ray-Gallet D, Almouzni G, et al. : Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell. 2004; 116 (1): 51–61. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 4. Banumathy G, Somaiah N, Zhang R, et al. : Human UBN1 is an ortholog of yeast Hpc2p and has an essential role in the HIRA/ASF1a chromatin-remodeling pathway in senescent cells. Mol Cell Biol. 2009; 29 (3): 758–70. PubMed Abstract | Publisher Full Text | Free Full Text 5. Ricketts MD, Frederick B, Hoff H, et al. : Ubinuclein-1 confers histone H3.3-specific-binding by the HIRA histone chaperone complex. Nat Commun. 2015; 6 : 7711. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 6. Pchelintsev NA, McBryan T, Rai TS, et al. : Placing the HIRA histone chaperone complex in the chromatin landscape. Cell Rep. 2013; 3 (4): 1012–9. PubMed Abstract | Publisher Full Text | Free Full Text 7. Adam S, Polo SE, Almouzni G: Transcription recovery after DNA damage requires chromatin priming by the H3.3 histone chaperone HIRA. Cell. 2013; 155 (1): 94–106. PubMed Abstract | Publisher Full Text 8. Zhang H, Gan H, Wang Z, et al. : RPA Interacts with HIRA and Regulates H3.3 Deposition at Gene Regulatory Elements in Mammalian Cells. Mol Cell. 2017; 65 (2): 272–84. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 9. Roberts C, Daw SC, Halford S, et al. : Cloning and developmental expression analysis of chick Hira ( Chira ), a candidate gene for DiGeorge syndrome. Hum Mol Genet. 1997; 6 (2): 237–45. PubMed Abstract | Publisher Full Text 10. Farrell MJ, Stadt H, Wallis KT, et al. : HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation. Circ Res. 1999; 84 (2): 127–35. PubMed Abstract | Publisher Full Text 11. Zhang R, Poustovoitov MV, Ye X, et al. : Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell. 2005; 8 (1): 19–30. PubMed Abstract | Publisher Full Text 12. Lee JS, Zhang Z: O-linked N -acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence. Proc Natl Acad Sci U S A. 2016; 113 (23): E3213–20. PubMed Abstract | Publisher Full Text | Free Full Text 13. Duarte LF, Young AR, Wang Z, et al. : Histone H3.3 and its proteolytically processed form drive a cellular senescence programme. Nat Commun. 2014; 5 : 5210. PubMed Abstract | Publisher Full Text | Free Full Text 14. Rai TS, Cole JJ, Nelson DM, et al. : HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes Dev. 2014; 28 (24): 2712–25. PubMed Abstract | Publisher Full Text | Free Full Text 15. Elsheikh SE, Green AR, Rakha EA, et al. : Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res. 2009; 69 (9): 3802–9. PubMed Abstract | Publisher Full Text 16. Stroud H, Otero S, Desvoyes B, et al. : Genome-wide analysis of histone H3.1 and H3.3 variants in Arabidopsis thaliana . Proc Natl Acad Sci U S A. 2012; 109 (14): 5370–5. PubMed Abstract | Publisher Full Text | Free Full Text 17. Wollmann H, Stroud H, Yelagandula R, et al. : The histone H3 variant H3.3 regulates gene body DNA methylation in Arabidopsis thaliana . Genome Biol. 2017; 18 (1): 94. PubMed Abstract | Publisher Full Text | Free Full Text 18. Braunschweig U, Hogan GJ, Pagie L, et al. : Histone H1 binding is inhibited by histone variant H3.3. EMBO J. 2009; 28 (23): 3635–45. PubMed Abstract | Publisher Full Text | Free Full Text 19. Yang X, Khosravi-Far R, Chang HY, et al. : Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell. 1997; 89 (7): 1067–76. PubMed Abstract | Publisher Full Text | Free Full Text 20. Xue Y, Gibbons R, Yan Z, et al. : The ATRX syndrome protein forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies. Proc Natl Acad Sci U S A. 2003; 100 (19): 10635–40. PubMed Abstract | Publisher Full Text | Free Full Text 21. Tang J, Wu S, Liu H, et al. : A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein. J Biol Chem. 2004; 279 (19): 20369–77. PubMed Abstract | Publisher Full Text 22. Elsässer SJ, Huang H, Lewis PW, et al. : DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition. Nature. 2012; 491 (7425): 560–5. PubMed Abstract | Publisher Full Text | Free Full Text 23. Goldberg AD, Banaszynski LA, Noh KM, et al. : Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell. 2010; 140 (5): 678–91. PubMed Abstract | Publisher Full Text | Free Full Text 24. Drané P, Ouararhni K, Depaux A, et al. : The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev. 2010; 24 (12): 1253–65. PubMed Abstract | Publisher Full Text | Free Full Text 25. Lewis PW, Elsaesser SJ, Noh KM, et al. : Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci U S A. 2010; 107 (32): 14075–80. PubMed Abstract | Publisher Full Text | Free Full Text 26. Dhayalan A, Tamas R, Bock I, et al. : The ATRX-ADD domain binds to H3 tail peptides and reads the combined methylation state of K4 and K9. Hum Mol Genet. 2011; 20 (11): 2195–203. PubMed Abstract | Publisher Full Text | Free Full Text 27. Eustermann S, Yang JC, Law MJ, et al. : Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin. Nat Struct Mol Biol. 2011; 18 (7): 777–82. PubMed Abstract | Publisher Full Text 28. Iwase S, Xiang B, Ghosh S, et al. : ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome. Nat Struct Mol Biol. 2011; 18 (7): 769–76. PubMed Abstract | Publisher Full Text | Free Full Text 29. Law MJ, Lower KM, Voon HP, et al. : ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. Cell. 2010; 143 (3): 367–78. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 30. Liu CP, Xiong C, Wang M, et al. : Structure of the variant histone H3.3-H4 heterodimer in complex with its chaperone DAXX. Nat Struct Mol Biol. 2012; 19 (12): 1287–92. PubMed Abstract | Publisher Full Text | Free Full Text 31. Gibbons RJ, Higgs DR: Molecular-clinical spectrum of the ATR-X syndrome. Am J Med Genet. 2000; 97 (3): 204–12. PubMed Abstract | <a target=\"xrefwindow\" id=\"d1041607e1739\" href=\"https://doi.org/10.1002/1096-8628(200023)97:3 Publisher Full Text 32. Jiao Y, Shi C, Edil BH, et al. : DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011; 331 (6021): 1199–203. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 33. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al. : K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012; 124 (3): 439–47. PubMed Abstract | Publisher Full Text | Free Full Text 34. Johnson BE, Mazor T, Hong C, et al. : Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014; 343 (6167): 189–93. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 35. Wu G, Diaz AK, Paugh BS, et al. : The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet. 2014; 46 (5): 444–50. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 36. Schwartzentruber J, Korshunov A, Liu XY, et al. : Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012; 482 (7384): 226–31. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 37. Heaphy CM, de Wilde RF, Jiao XY, et al. : Altered telomeres in tumors with ATRX and DAXX mutations. Science. 2011; 333 (333): 425. PubMed Abstract | Publisher Full Text | Free Full Text 38. Lin CW, Wang LK, Wang SP, et al. : Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis. Nat Commun. 2016; 7 : 13867. PubMed Abstract | Publisher Full Text | Free Full Text 39. Benitez JA, Ma J, D'Antonio M, et al. : PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3. Nat Commun. 2017; 8 : 15223. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 40. Puto LA, Brognard J, Hunter T: Transcriptional Repressor DAXX Promotes Prostate Cancer Tumorigenicity via Suppression of Autophagy. J Biol Chem. 2015; 290 (25): 15406–20. PubMed Abstract | Publisher Full Text | Free Full Text 41. Athwal RK, Walkiewicz MP, Baek S, et al. : CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells. Epigenetics Chromatin. 2015; 8 : 2. PubMed Abstract | Publisher Full Text | Free Full Text 42. Lacoste N, Woolfe A, Tachiwana H, et al. : Mislocalization of the centromeric histone variant CenH3/CENP-A in human cells depends on the chaperone DAXX. Mol Cell. 2014; 53 (4): 631–44. PubMed Abstract | Publisher Full Text 43. Shrestha RL, Ahn GS, Staples MI, et al. : Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells. Oncotarget. 2017; 8 (29): 46781–800. PubMed Abstract | Publisher Full Text | Free Full Text 44. Nakashima T, Tomita H, Hirata A, et al. : Promotion of cell proliferation by the proto-oncogene DEK enhances oral squamous cell carcinogenesis through field cancerization. Cancer Med. 2017; 6 (10): 2424–39. PubMed Abstract | Publisher Full Text | Free Full Text 45. Khodadoust MS, Verhaegen M, Kappes F, et al. : Melanoma proliferation and chemoresistance controlled by the DEK oncogene. Cancer Res. 2009; 69 (16): 6405–13. PubMed Abstract | Publisher Full Text | Free Full Text 46. von Lindern M, Fornerod M, van Baal S, et al. : The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA. Mol Cell Biol. 1992; 12 (4): 1687–97. PubMed Abstract | Publisher Full Text | Free Full Text 47. Saito S, Cigdem S, Okuwaki M, et al. : Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway. Mol Cell Biol. 2016; 36 (13): 1820–35. PubMed Abstract | Publisher Full Text | Free Full Text 48. Piredda ML, Catalano G, Ciardi C, et al. : Identification of a potential topoisomerase II \"hotspot\" DNA region in the DEK gene in two t(6;9)-positive therapy-related myeloid neoplasms. Ann Hematol. 2017; 96 (1): 155–7. PubMed Abstract | Publisher Full Text 49. Qin H, Malek S, Cowell JK, et al. : Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model. Oncogene. 2016; 35 (43): 5686–91. PubMed Abstract | Publisher Full Text | Free Full Text 50. Campregher PV, Halley ND, Vieira GA, et al. : Identification of a novel fusion TBL1XR1-PDGFRB in a patient with acute myeloid leukemia harboring the DEK-NUP214 fusion and clinical response to dasatinib. Leuk Lymphoma. 2017; 58 (12): 2969–72. PubMed Abstract | Publisher Full Text 51. Wise-Draper TM, Allen HV, Thobe MN, et al. : The human DEK proto-oncogene is a senescence inhibitor and an upregulated target of high-risk human papillomavirus E7. J Virol. 2005; 79 (22): 14309–17. PubMed Abstract | Publisher Full Text | Free Full Text 52. Bui M, Dimitriadis EK, Hoischen C, et al. : Cell-cycle-dependent structural transitions in the human CENP-A nucleosome in vivo . Cell. 2012; 150 (2): 317–26. PubMed Abstract | Publisher Full Text | Free Full Text 53. Hu Z, Huang G, Sadanandam A, et al. : The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer. Breast Cancer Res. 2010; 12 (2): R18. PubMed Abstract | Publisher Full Text | Free Full Text 54. Hu B, Wang Q, Wang Y, et al. : Holliday junction-recognizing protein promotes cell proliferation and correlates with unfavorable clinical outcome of hepatocellular carcinoma. Onco Targets Ther. 2017; 10 : 2601–7. PubMed Abstract | Publisher Full Text | Free Full Text 55. Rouam S, Moreau T, Broët P: Identifying common prognostic factors in genomic cancer studies: a novel index for censored outcomes. BMC Bioinformatics. 2010; 11 : 150. PubMed Abstract | Publisher Full Text | Free Full Text 56. Valente V, Serafim RB, de Oliveira LC, et al. : Modulation of HJURP (Holliday Junction-Recognizing Protein) levels is correlated with glioblastoma cells survival. PLoS One. 2013; 8 (4): e62200. PubMed Abstract | Publisher Full Text | Free Full Text 57. de Tayrac M, Saikali S, Aubry M, et al. : Prognostic significance of EDN/RB, HJURP, p60/CAF-1 and PDLI4, four new markers in high-grade gliomas. PLoS One. 2013; 8 (9): e73332. PubMed Abstract | Publisher Full Text | Free Full Text 58. Montes de Oca R, Gurard-Levin ZA, Berger F, et al. : The histone chaperone HJURP is a new independent prognostic marker for luminal A breast carcinoma. Mol Oncol. 2015; 9 (3): 657–74. PubMed Abstract | Publisher Full Text | Free Full Text 59. Zhou D, Tang W, Liu X, et al. : Clinical verification of plasma messenger RNA as novel noninvasive biomarker identified through bioinformatics analysis for lung cancer. Oncotarget. 2017; 8 (27): 43978–89. PubMed Abstract | Publisher Full Text | Free Full Text 60. Cao R, Wang G, Qian K, et al. : Silencing of HJURP induces dysregulation of cell cycle and ROS metabolism in bladder cancer cells via PPARγ-SIRT1 feedback loop. J Cancer. 2017; 8 (12): 2282–95. PubMed Abstract | Publisher Full Text | Free Full Text 61. Jansen LE, Black BE, Foltz DR, et al. : Propagation of centromeric chromatin requires exit from mitosis. J Cell Biol. 2007; 176 (6): 795–805. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 62. Filipescu D, Naughtin M, Podsypanina K, et al. : Essential role for centromeric factors following p53 loss and oncogenic transformation. Genes Dev. 2017; 31 (5): 463–80. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 63. Pan WW, Zhou JJ, Liu XM, et al. : Death domain-associated protein DAXX promotes ovarian cancer development and chemoresistance. J Biol Chem. 2013; 288 (19): 13620–30. PubMed Abstract | Publisher Full Text | Free Full Text 64. Sawatsubashi S, Murata T, Lim J, et al. : A histone chaperone, DEK, transcriptionally coactivates a nuclear receptor. Genes Dev. 2010; 24 (2): 159–70. PubMed Abstract | Publisher Full Text | Free Full Text 65. Sandén C, Gullberg U: The DEK oncoprotein and its emerging roles in gene regulation. Leukemia. 2015; 29 (8): 1632–6. PubMed Abstract | Publisher Full Text 66. Böhm F, Kappes F, Scholten I, et al. : The SAF-box domain of chromatin protein DEK. Nucleic Acids Res. 2005; 33 (3): 1101–10. PubMed Abstract | Publisher Full Text | Free Full Text 67. Waldmann T, Eckerich C, Baack M, et al. : The ubiquitous chromatin protein DEK alters the structure of DNA by introducing positive supercoils. J Biol Chem. 2002; 277 (28): 24988–94. PubMed Abstract | Publisher Full Text 68. Ivanauskiene K, Delbarre E, McGhie JD, et al. : The PML-associated protein DEK regulates the balance of H3.3 loading on chromatin and is important for telomere integrity. Genome Res. 2014; 24 (10): 1584–94. PubMed Abstract | Publisher Full Text | Free Full Text 69. Xu X, Zou L, Yao Q, et al. : Silencing DEK downregulates cervical cancer tumorigenesis and metastasis via the DEK/p-Ser9-GSK-3β/p-Tyr216-GSK-3β/β-catenin axis. Oncol Rep. 2017; 38 (2): 1035–42. PubMed Abstract | Publisher Full Text 70. Feng T, Liu Y, Li C, et al. : DEK proto-oncogene is highly expressed in astrocytic tumors and regulates glioblastoma cell proliferation and apoptosis. Tumour Biol. 2017; 39 (7): 1010428317716248. PubMed Abstract | Publisher Full Text 71. Sun J, Bi F, Yang Y, et al. : DEK protein overexpression predicts poor prognosis in pancreatic ductal adenocarcinoma. Oncol Rep. 2017; 37 (2): 857–64. PubMed Abstract | Publisher Full Text 72. Qiao MX, Li C, Zhang AQ, et al. : Regulation of DEK expression by AP-2α and methylation level of DEK promoter in hepatocellular carcinoma. Oncol Rep. 2016; 36 (4): 2382–90. PubMed Abstract | Publisher Full Text 73. Ou Y, Xia R, Kong F, et al. : Overexpression of DEK is an indicator of poor prognosis in patients with gastric adenocarcinoma. Oncol Lett. 2016; 11 (3): 1823–8. PubMed Abstract | Publisher Full Text | Free Full Text 74. Yu L, Huang X, Zhang W, et al. : Critical role of DEK and its regulation in tumorigenesis and metastasis of hepatocellular carcinoma. Oncotarget. 2016; 7 (18): 26844–55. PubMed Abstract | Publisher Full Text | Free Full Text 75. Wise-Draper TM, Mintz-Cole RA, Morris TA, et al. : Overexpression of the cellular DEK protein promotes epithelial transformation in vitro and in vivo . Cancer Res. 2009; 69 (5): 1792–9. PubMed Abstract | Publisher Full Text | Free Full Text 76. Henikoff S, Furuyama T: Epigenetic inheritance of centromeres. Cold Spring Harb Symp Quant Biol. 2010; 75 : 51–60. PubMed Abstract | Publisher Full Text 77. Foltz DR, Jansen LE, Bailey AO, et al. : Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP. Cell. 2009; 137 (3): 472–84. PubMed Abstract | Publisher Full Text | Free Full Text 78. Shuaib M, Ouararhni K, Dimitrov S, et al. : HJURP binds CENP-A via a highly conserved N-terminal domain and mediates its deposition at centromeres. Proc Natl Acad Sci U S A. 2010; 107 (4): 1349–54. PubMed Abstract | Publisher Full Text | Free Full Text 79. Silva MC, Bodor DL, Stellfox ME, et al. : Cdk activity couples epigenetic centromere inheritance to cell cycle progression. Dev Cell. 2012; 22 (1): 52–63. PubMed Abstract | Publisher Full Text 80. Stankovic A, Guo LY, Mata JF, et al. : A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly. Mol Cell. 2017; 65 (2): 231–46. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 81. Zasadzińska E, Barnhart-Dailey MC, Kuich PH, et al. : Dimerization of the CENP-A assembly factor HJURP is required for centromeric nucleosome deposition. EMBO J. 2013; 32 (15): 2113–24. PubMed Abstract | Publisher Full Text | Free Full Text 82. Zhang W, Mao JH, Zhu W, et al. : Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy. Nat Commun. 2016; 7 : 12619. PubMed Abstract | Publisher Full Text | Free Full Text 83. Huang W, Zhang H, Hao Y, et al. : A Non-Synonymous Single Nucleotide Polymorphism in the HJURP Gene Associated with Susceptibility to Hepatocellular Carcinoma among Chinese. PLoS One. 2016; 11 (2): e0148618. PubMed Abstract | Publisher Full Text | Free Full Text 84. Tomonaga T, Matsushita K, Yamaguchi S, et al. : Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Res. 2003; 63 (13): 3511–6. PubMed Abstract 85. Melters DP, Nye J, Zhao H, et al. : Chromatin Dynamics in Vivo : A Game of Musical Chairs. Genes (Basel). 2015; 6 (3): 751–76. PubMed Abstract | Publisher Full Text | Free Full Text 86. Arimura Y, Shirayama K, Horikoshi N, et al. : Crystal structure and stable property of the cancer-associated heterotypic nucleosome containing CENP-A and H3.3. Sci Rep. 2014; 4 (1): 7115. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 87. Xu M, Long C, Chen X, et al. : Partitioning of histone H3-H4 tetramers during DNA replication-dependent chromatin assembly. Science. 2010; 328 (5974): 94–8. PubMed Abstract | Publisher Full Text 88. Huang C, Zhang Z, Xu M, et al. : H3.3-H4 tetramer splitting events feature cell-type specific enhancers. PLoS Genet. 2013; 9 (6): e1003558. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 89. Katan-Khaykovich Y, Struhl K: Splitting of H3-H4 tetramers at transcriptionally active genes undergoing dynamic histone exchange. Proc Natl Acad Sci U S A. 2011; 108 (4): 1296–301. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 90. Bui M, Pitman M, Nuccio A, et al. : Internal modifications in the CENP-A nucleosome modulate centromeric dynamics. Epigenetics Chromatin. 2017; 10 : 17. PubMed Abstract | Publisher Full Text | Free Full Text 91. Niikura Y, Kitagawa R, Kitagawa K: CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions. Cell Rep. 2016; 15 (1): 61–76. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 92. Niikura Y, Kitagawa R, Kitagawa K: CENP-A Ubiquitylation Is Required for CENP-A Deposition at the Centromere. Dev Cell. 2017; 40 (1): 7–8. PubMed Abstract | Publisher Full Text 93. Yu Z, Zhou X, Wang W, et al. : Dynamic phosphorylation of CENP-A at Ser68 orchestrates its cell-cycle-dependent deposition at centromeres. Dev Cell. 2015; 32 (1): 68–81. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 94. Zhao H, Winogradoff D, Bui M, et al. : Promiscuous Histone Mis-Assembly Is Actively Prevented by Chaperones. J Am Chem Soc. 2016; 138 (40): 13207–18. PubMed Abstract | Publisher Full Text 95. Takada M, Zhang W, Suzuki A, et al. : FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A. Cancer Res. 2017; 77 (18): 4881–93. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 96. Loyola A, Bonaldi T, Roche D, et al. : PTMs on H3 variants before chromatin assembly potentiate their final epigenetic state. Mol Cell. 2006; 24 (2): 309–16. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 97. Kang B, Pu M, Hu G, et al. : Phosphorylation of H4 Ser 47 promotes HIRA-mediated nucleosome assembly. Genes Dev. 2011; 25 (13): 1359–64. PubMed Abstract | Publisher Full Text | Free Full Text 98. Quénet D, Walkiewicz M, Dalal Y: Chromatin at the Intersection of Disease and Therapy. In Toxicology and Epigenetics . John Wiley & Sons, Ltd. 2012; 51–71. Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 02 Feb 2018 ADD YOUR COMMENT Comment Author details Author details 1 Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Jonathan Nye Roles: Conceptualization, Writing – Original Draft Preparation Daniël P. Melters Roles: Writing – Original Draft Preparation Yamini Dalal Roles: Conceptualization, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information All authors were supported by the Intramural Research Program of the Center for Cancer Research at the National Cancer Institute The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 02 Feb 2018, 7:141 https://doi.org/10.12688/f1000research.12833.1 Copyright © 2018 Nye J et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Nye J, Melters DP and Dalal Y. The Art of War: harnessing the epigenome against cancer [version 1; peer review: 4 approved] . F1000Research 2018, 7 (F1000 Faculty Rev):141 ( https://doi.org/10.12688/f1000research.12833.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Editorial Note on the Review Process Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Reviewers who approved this article Zhiguo Zhang , Departments of Pediatrics and Genetics and Development, , Institute for Cancer Genetics, Irving Cancer Research Center, College of Surgeons and Physicians, Columbia University, USA Competing interests: No competing interests were declared. (for version 1) Peter Adams , Beatson Institute for Canc, UK Competing interests: No competing interests were declared. (for version 1) Genevieve Almouzni , Equipe Labellisée Ligue contre le Cancer; Sorbonne Universités, Institut Curie, PSL Research University, France Competing interests: No competing interests were declared. (for version 1) Sandra B Hake , Center for Integrated Protein Science Munich (CIPSM), Ludwig Maximilians University Munich, Germany Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 02 Feb 2018 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 4 Version 1 02 Feb 18 Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Zhiguo Zhang , Departments of Pediatrics and Genetics and Development, , Institute for Cancer Genetics, Irving Cancer Research Center, College of Surgeons and Physicians, Columbia University, USA Competing interests: No competing interests were declared. View more View less Peter Adams , Beatson Institute for Canc, UK Competing interests: No competing interests were declared. View more View less Genevieve Almouzni , Equipe Labellisée Ligue contre le Cancer; Sorbonne Universités, Institut Curie, PSL Research University, France Competing interests: No competing interests were declared. View more View less Sandra B Hake , Center for Integrated Protein Science Munich (CIPSM), Ludwig Maximilians University Munich, Germany Competing interests: No competing interests were declared. View more View less Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = \"The Art of War: harnessing the epigenome...\".replace(\"'\", ''); var linkedInUrl = \"http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/7-141/v1\" + \"&title=\" + encodeURIComponent(lTitle) + \"&summary=\" + encodeURIComponent('Read the article by '); var deliciousUrl = \"https://del.icio.us/post?url=https://f1000research.com/articles/7-141/v1&title=\" + encodeURIComponent(lTitle); var redditUrl = \"http://reddit.com/submit?url=https://f1000research.com/articles/7-141/v1\" + \"&title=\" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Nye J et al.'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : \"facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com\", services_expanded : \"facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com\", services_custom : [ { name: \"LinkedIn\", url: linkedInUrl, icon:\"/img/icon/at_linkedin.svg\" }, { name: \"Mendeley\", url: \"http://www.mendeley.com/import/?url=https://f1000research.com/articles/7-141/v1/mendeley\", icon:\"/img/icon/at_mendeley.svg\" }, { name: \"Reddit\", url: redditUrl, icon:\"/img/icon/at_reddit.svg\" }, ] }; var addthis_share = { url: \"https://f1000research.com/articles/7-141\", templates : { twitter : \"The Art of War: harnessing the epigenome against cancer. Nye J et al., published by \" + \"@F1000Research\" + \", https://f1000research.com/articles/7-141/v1\" } }; if (typeof(addthis) != \"undefined\"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(\".f1r-shares-twitter\").attr(\"href\", \"https://twitter.com/intent/tweet?text=\" + addthis_share.templates.twitter); $(\".f1r-shares-facebook\").attr(\"href\", \"https://www.facebook.com/sharer/sharer.php?u=\" + addthis_share.url); $(\".f1r-shares-linkedin\").attr(\"href\", addthis_config.services_custom[0].url); $(\".f1r-shares-reddit\").attr(\"href\", addthis_config.services_custom[2].url); $(\".f1r-shares-mendelay\").attr(\"href\", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(\".addthis_button_expanded\").each(function(){ var count = $(this).text(); if (count !== \"\" && count != \"0\") $(this).removeClass(\"is-hidden\"); else $(this).addClass(\"is-hidden\"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get(\"/articles/acj/12833/13906\") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay(\"faculty-reviews\", \"article\", \"13906\"); $(document).ready(function() { $( \"#frame1\" ).on('load', function() { var mydiv = $(this).contents().find(\"div\"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(\".interactive-living-figure-label .icon-more-info\"), titleLivingFigure = tooltipLivingFigure.attr(\"title\"); tooltipLivingFigure.simpletip({ fixed: true, position: [\"-115\", \"30\"], baseClass: 'small-tooltip', content:titleLivingFigure + \" \" }); tooltipLivingFigure.removeAttr(\"title\"); $(\"body\").on(\"click\", \".cite-living-figure\", function(e) { e.preventDefault(); var ref = $(this).attr(\"data-ref\"); $(this).closest(\".living-figure-list-container\").find(\"#\" + ref).fadeIn(200); }); $(\"body\").on(\"click\", \".close-cite-living-figure\", function(e) { e.preventDefault(); $(this).closest(\".popup-window-wrapper\").fadeOut(200); }); $(document).on(\"mouseup\", function(e) { var metricsContainer = $(\".article-metrics-popover-wrapper\"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(\".article-metrics-close-button\").click(); } }); var articleId = $('#articleId').val(); if($(\"#main-article-count-box\").attachArticleMetrics) { $(\"#main-article-count-box\").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(\".new_figshare_widget\"); if (figshareWidget.length > 0) { window.figshare.load(\"f1000\", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr(\"figshare_articleId\") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { \"30471\": 0, \"30472\": 0, \"30473\": 0, \"30474\": 0, }; $(\".referee-response-container,.js-referee-report\").each(function(index, el) { var reportId = $(el).attr(\"data-reportid\"), reportCount = reportIds[reportId] || 0; $(el).find(\".comments-count-container,.js-referee-report-views\").html(reportCount); }); var uuidInput = $(\"#article_uuid\"), oldUUId = uuidInput.val(), newUUId = \"18d417f6-ee0a-4ad5-8f82-58a096a11c42\"; uuidInput.val(newUUId); $(\"a[href*='article_uuid=']\").each(function(index, el) { var newHref = $(el).attr(\"href\").replace(oldUUId, newUUId); $(el).attr(\"href\", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: \"f1000research\", displayName: \"F1000Research\", hostName: \"f1000research.com\", id: \"1\", editorialEmail: \"research@f1000.com\", infoEmail: \"info@f1000.com\", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(\".cookie-warning\").is(\":visible\")) { $(\".sticky\").css(\"margin-bottom\", \"35px\"); $(\".devices\").addClass(\"devices-and-cookie-warning\"); } $(\".cookie-warning .close-button\").click(function (e) { $(\".devices\").removeClass(\"devices-and-cookie-warning\"); $(\".sticky\").css(\"margin-bottom\", \"0\"); }); $(\"#tweeter-feed .tweet-message\").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(\".partner\").on(\"mouseenter mouseleave\", function() { $(this).find(\".gray-scale, .colour\").toggleClass(\"is-hidden\"); }); }); <!-- Sign in --> Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $(\"a[id=googleSignInButton]\").click(function(event){ event.preventDefault(); $(\"input[id=oAuthSystem]\").val(\"GOOGLE\"); $(\"form[id=oAuthForm]\").submit(); }); $(\"a[id=facebookSignInButton]\").click(function(event){ event.preventDefault(); $(\"input[id=oAuthSystem]\").val(\"FACEBOOK\"); $(\"form[id=oAuthForm]\").submit(); }); $(\"a[id=orcidSignInButton]\").click(function(event){ event.preventDefault(); $(\"input[id=oAuthSystem]\").val(\"ORCID\"); $(\"form[id=oAuthForm]\").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($(\"#sign-in-form-gfb-popup\")); $(\".target-field\").each(function () { var uris = $(this).val().split(\"/\"); if (uris.pop() === \"login\") { $(this).val(uris.toString().replace(\",\",\"/\")); } }); });","source_license":"CC-BY-4.0","license_restricted":false}