MER57E3 transposable element subfamily co-opted for gene regulation in human early neural development

MER57E3 transposable element subfamily co-opted for gene regulation in human early neural development | 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 MER57E3 transposable element subfamily co-opted for gene regulation in human early neural development Michelle Almeida da Paz, Umut Yildiz, Minyoung Kim, Víctor Campos-Fornés, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6279618/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Jan, 2026 Read the published version in Genome Biology → Version 1 posted 9 You are reading this latest preprint version Abstract Background Long dismissed as mere genomic parasites, transposable elements (TEs) are now recognized as major drivers of genome evolution. TEs serve as a source of cell-type specific cis -regulatory elements, influencing gene expression and observable phenotypes. However, the precise TE regulatory roles in different contexts remain largely unexplored and the impact of TEs on transcriptional regulatory networks and contribution to disease risk is likely deeply underestimated. Results Using a multimapper-aware strategy, we systematically characterised the epigenetic profile of TEs in the brain. This analysis revealed that MER57E3, a primate-specific TE subfamily, exhibits strong enrichment for active, and absence of repressive, histone modifications across six brain cell types. MER57E3 copies are predominantly located near zinc finger genes and enriched for homeodomain motifs recognized by brain-specific transcription factors, including GBX1 and BSX. Upon CRISPR interference (CRISPRi) targeting specific MER57E3 copies, RNA-seq analysis demonstrated downregulation of the key neurogenesis-related genes PAX6 and NEUROG2 . Conclusions Our data indicate that members of the MER57E3 TE subfamily regulate the expression of critical neurogenesis genes during neural progenitor cell (NPC) development. Moreover, this study emphasises the importance of characterising TEs, offering new insights into how their epigenetic dysregulation may contribute to pathogenesis of neurodevelopmental disorders. Transposable element epigenetic profile gene regulation neural progenitor cell (NPC) early neural development targeted CRISPR interference (CRISPRi) Full Text Additional Declarations No competing interests reported. Supplementary Files Additionalfile1.xlsx Additional file 1: Suppl. Tables 1–10 Additionalfile2.docx Additional file 2: Suppl. Figures 1–5 Cite Share Download PDF Status: Published Journal Publication published 31 Jan, 2026 Read the published version in Genome Biology → Version 1 posted Editorial decision: Revision requested 04 Jun, 2025 Reviews received at journal 21 May, 2025 Reviews received at journal 06 May, 2025 Reviewers agreed at journal 17 Apr, 2025 Reviewers agreed at journal 17 Apr, 2025 Reviewers invited by journal 15 Apr, 2025 Editor assigned by journal 28 Mar, 2025 Submission checks completed at journal 25 Mar, 2025 First submitted to journal 21 Mar, 2025 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-6279618","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":435351243,"identity":"29d6cbcc-6dfa-468f-b19b-804bf0e15220","order_by":0,"name":"Michelle Almeida da Paz","email":"","orcid":"","institution":"Graz University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Michelle","middleName":"Almeida da","lastName":"Paz","suffix":""},{"id":435351245,"identity":"b67c3e5d-b136-4dfd-910d-0b2ab7ffd30d","order_by":1,"name":"Umut Yildiz","email":"","orcid":"","institution":"European Molecular Biology Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Umut","middleName":"","lastName":"Yildiz","suffix":""},{"id":435351248,"identity":"81f666d0-2eb8-4981-b8f5-3e90b1389bf2","order_by":2,"name":"Minyoung Kim","email":"","orcid":"","institution":"European Molecular Biology Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Minyoung","middleName":"","lastName":"Kim","suffix":""},{"id":435351250,"identity":"9dc651b1-acc8-4274-999e-0a8bc3124fea","order_by":3,"name":"Víctor Campos-Fornés","email":"","orcid":"","institution":"European Molecular Biology Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Víctor","middleName":"","lastName":"Campos-Fornés","suffix":""},{"id":435351255,"identity":"a7bd5274-c007-4180-a342-0af3fa06e62a","order_by":4,"name":"Marina Pinkasz","email":"","orcid":"","institution":"European Molecular Biology Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Marina","middleName":"","lastName":"Pinkasz","suffix":""},{"id":435351256,"identity":"6039cda6-03e5-4fa1-ae94-4d521cd78389","order_by":5,"name":"Thomas Dahlet","email":"","orcid":"","institution":"European Molecular Biology Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Dahlet","suffix":""},{"id":435351257,"identity":"5e91ddd5-dbcc-404b-b858-c2dbb02ff225","order_by":6,"name":"Kyung-Min Noh","email":"","orcid":"","institution":"European Molecular Biology Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Kyung-Min","middleName":"","lastName":"Noh","suffix":""},{"id":435351258,"identity":"390706f4-2e5c-41a0-a02b-8df727d05032","order_by":7,"name":"Leila Taher","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYBACPgbGxgMghgEDA+MDorSwMTA2HABpAGphNjgAEz6AUwNIC1gerIVNgjgt7M0NB34w/JE3Z+99Vv2xrTafv/8A4+cP+LTwHGw42MNgYLiz57jZjYNtxy1nHDjAjLAOmxaJxIYDPAwGjBtupLEBtRwzYDjYwIBfi/zDhoN/GAzsN9x/xlYA0iJ/mIH5B35bGBsOA21J3HCDjY3hYFuNgcEx5HDA6pfEhsMyBsbJG86kMUucOXfAwPAMY5vFGTxa+NmPP3z4pkLOdsPxY4wfKsrqDOTOHz58owKPFggwgLMOAzFjA0ENyKCOJNWjYBSMglEwMgAAJ8hT/NrlmosAAAAASUVORK5CYII=","orcid":"","institution":"Graz University of Technology","correspondingAuthor":true,"prefix":"","firstName":"Leila","middleName":"","lastName":"Taher","suffix":""}],"badges":[],"createdAt":"2025-03-21 17:53:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6279618/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6279618/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13059-026-03946-x","type":"published","date":"2026-01-31T15:58:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":101690829,"identity":"80e5aef3-aab5-4e41-9f41-776ad7fda5cb","added_by":"auto","created_at":"2026-02-02 16:09:34","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1082501,"visible":true,"origin":"","legend":"","description":"","filename":"AlmeidaDaPaz21032025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6279618/v1_covered_9002998d-fe4e-4bd4-8ffc-aaf2b83bef39.pdf"},{"id":80024837,"identity":"60b12bb6-31f7-4923-8bf8-a67f4e3bb709","added_by":"auto","created_at":"2025-04-07 06:00:55","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10507429,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 1: Suppl. 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TEs serve as a source of cell-type specific \u003cem\u003ecis\u003c/em\u003e-regulatory elements, influencing gene expression and observable phenotypes. However, the precise TE regulatory roles in different contexts remain largely unexplored and the impact of TEs on transcriptional regulatory networks and contribution to disease risk is likely deeply underestimated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eUsing a multimapper-aware strategy, we systematically characterised the epigenetic profile of TEs in the brain. This analysis revealed that MER57E3, a primate-specific TE subfamily, exhibits strong enrichment for active, and absence of repressive, histone modifications across six brain cell types. MER57E3 copies are predominantly located near zinc finger genes and enriched for homeodomain motifs recognized by brain-specific transcription factors, including GBX1 and BSX. Upon CRISPR interference (CRISPRi) targeting specific MER57E3 copies, RNA-seq analysis demonstrated downregulation of the key neurogenesis-related genes \u003cem\u003ePAX6\u003c/em\u003e and \u003cem\u003eNEUROG2\u003c/em\u003e.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur data indicate that members of the MER57E3 TE subfamily regulate the expression of critical neurogenesis genes during neural progenitor cell (NPC) development. Moreover, this study emphasises the importance of characterising TEs, offering new insights into how their epigenetic dysregulation may contribute to pathogenesis of neurodevelopmental disorders.\u003c/p\u003e","manuscriptTitle":"MER57E3 transposable element subfamily co-opted for gene regulation in human early neural development","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-07 06:00:49","doi":"10.21203/rs.3.rs-6279618/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-04T13:25:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-21T16:05:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-06T19:05:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333344734651072315273444528488072751913","date":"2025-04-17T15:18:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222414991124170981945190150241344852610","date":"2025-04-17T15:04:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-15T13:16:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-28T12:28:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-25T09:43:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Genome Biology","date":"2025-03-21T17:41:22+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":"72c1d403-d73d-4671-a207-85d88de84459","owner":[],"postedDate":"April 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:06:28+00:00","versionOfRecord":{"articleIdentity":"rs-6279618","link":"https://doi.org/10.1186/s13059-026-03946-x","journal":{"identity":"genome-biology","isVorOnly":false,"title":"Genome Biology"},"publishedOn":"2026-01-31 15:58:04","publishedOnDateReadable":"January 31st, 2026"},"versionCreatedAt":"2025-04-07 06:00:49","video":"","vorDoi":"10.1186/s13059-026-03946-x","vorDoiUrl":"https://doi.org/10.1186/s13059-026-03946-x","workflowStages":[]},"version":"v1","identity":"rs-6279618","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6279618","identity":"rs-6279618","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}