Common rules of the organization and architecture of cis-regulatory modules in the human and mouse genomes

Common rules of the organization and architecture of cis-regulatory modules in the human and mouse genomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Common rules of the organization and architecture of cis-regulatory modules in the human and mouse genomes Sisi Yuan, Pengyu Ni, Zhengchang Su This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4510188/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 13 You are reading this latest preprint version Abstract Background We have recently predicted comprehensive maps of cis -regulatory modules (CRMs) and constituent transcription factor (TF) binding sites (TFBSs) in the human and mouse genomes, enabling us to investigate the organization and architecture of the CRMs in both genomes. Results We reveal common rules of the organization and architecture of CRMs in the genomes. 1) The numbers and lengths of CRMs and genes on chromosomes are correlated with the sizes of chromosomes. 2) CRMs are unevenly but correlatedly distributed with genes along chromosomes. 3) The number of CRMs and genes within topologically associating domains (TADs) shows a stronger correlation than those in non-TAD regions. 4) CRMs are slightly biasedly distributed downstream of their nearest transcription start sites. 5) A considerable portion (~ 7%) of CRMs overlap core promoters, thus, CRMs can be classified into core promoter-containing (CPC) and core promoter-lacking (CPL) categories. 6) Most (> 90%) of core promoters overlap long CRMs, hence, they rarely exist alone. 7) CPC CRMs tend to be longer than CPL CRMs. 8) TFBSs exhibit extensive overlaps, forming longer TFBS islands. 9) TFBS islands comprise less than half of CRMs in length. 10) Spacers between TFBS islands are subject to similar evolutionary constraints as TFBS islands. Inter-TFBS spacers are less likely to overlap DNase I hypersensitive sites and TF footprints than TFBS islands, suggesting that they may play roles in transcriptional regulation other than direct TF binding. Conclusions The rules governing the organization and architecture of CRMs in the human and mouse genomes are highly conserved. cis-regulatory modules transcriptional regulation transcription factor binding sites inter-TFBS spacer Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigures05312024.docx SupplementaryTables05312024.xls Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 13 Feb, 2026 Reviews received at journal 13 Feb, 2026 Reviews received at journal 06 Feb, 2026 Reviews received at journal 04 Feb, 2026 Reviewers agreed at journal 28 Jan, 2026 Reviewers agreed at journal 23 Jan, 2026 Reviewers agreed at journal 23 Jan, 2026 Reviews received at journal 29 Mar, 2025 Reviewers agreed at journal 18 Mar, 2025 Reviewers invited by journal 31 Jul, 2024 Editor assigned by journal 04 Jun, 2024 Submission checks completed at journal 03 Jun, 2024 First submitted to journal 31 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4510188","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":313640258,"identity":"b2cd90dd-8b15-4400-abf2-ce59e6c2afde","order_by":0,"name":"Sisi Yuan","email":"","orcid":"","institution":"the University of North Carolina at Charlotte","correspondingAuthor":false,"prefix":"","firstName":"Sisi","middleName":"","lastName":"Yuan","suffix":""},{"id":313640259,"identity":"13b84c5f-a6a3-4132-af6f-633eb753aae4","order_by":1,"name":"Pengyu Ni","email":"","orcid":"","institution":"the University of North Carolina at 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chromosomes are correlated with the sizes of chromosomes. 2) CRMs are unevenly but correlatedly distributed with genes along chromosomes. 3) The number of CRMs and genes within topologically associating domains (TADs) shows a stronger correlation than those in non-TAD regions. 4) CRMs are slightly biasedly distributed downstream of their nearest transcription start sites. 5) A considerable portion (~\u0026thinsp;7%) of CRMs overlap core promoters, thus, CRMs can be classified into core promoter-containing (CPC) and core promoter-lacking (CPL) categories. 6) Most (\u0026gt;\u0026thinsp;90%) of core promoters overlap long CRMs, hence, they rarely exist alone. 7) CPC CRMs tend to be longer than CPL CRMs. 8) TFBSs exhibit extensive overlaps, forming longer TFBS islands. 9) TFBS islands comprise less than half of CRMs in length. 10) Spacers between TFBS islands are subject to similar evolutionary constraints as TFBS islands. Inter-TFBS spacers are less likely to overlap DNase I hypersensitive sites and TF footprints than TFBS islands, suggesting that they may play roles in transcriptional regulation other than direct TF binding.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe rules governing the organization and architecture of CRMs in the human and mouse genomes are highly conserved.\u003c/p\u003e","manuscriptTitle":"Common rules of the organization and architecture of cis-regulatory modules in the human and mouse genomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-14 18:06:54","doi":"10.21203/rs.3.rs-4510188/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-13T14:41:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-13T13:22:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-06T15:51:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-04T17:29:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315929828850552331552381993051603422713","date":"2026-01-28T13:08:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334416096729065780282887243482983028080","date":"2026-01-23T15:13:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246624344689914685331695730956326832969","date":"2026-01-23T14:12:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-30T01:23:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"92941221409226962982869336730406187526","date":"2025-03-18T17:38:19+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-31T14:40:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-04T13:56:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-03T09:34:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Genome Biology","date":"2024-05-31T16:21:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"genome-biology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"gbio","sideBox":"Learn more about [Genome Biology](https://genomebiology.biomedcentral.com/)","snPcode":"13059","submissionUrl":"https://submission.springernature.com/new-submission/13059/3","title":"Genome Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4e4b055-4dad-4d45-ad58-380690fdc230","owner":[],"postedDate":"June 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-02-13T14:54:11+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-14 18:06:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4510188","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4510188","identity":"rs-4510188","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}