{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T08:56:58Z","timestamp":1776329818032,"version":"3.50.1"},"posted":{"date-parts":[[2026,4,13]]},"group-title":"Cell Biology","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["NS108376"],"award-info":[{"award-number":["NS108376"]}]},{"name":"NIH","award":["GM154414"],"award-info":[{"award-number":["GM154414"]}]},{"name":"NIH","award":["P30 CA021765"],"award-info":[{"award-number":["P30 CA021765"]}]},{"name":"NSF","award":["CEE-EFRI: #1933402"],"award-info":[{"award-number":["CEE-EFRI: #1933402"]}]},{"DOI":"10.13039\/100002108","name":"Friedreich\u2019s ataxia research alliance","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100002108","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The American Lebanese Syrian Associated Charities at St. Jude"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  How genes are desilenced within mesoscale repressive chromatin is a crucial yet poorly understood phenomenon. Prevailing models posit that methylation of lysine-9 of histone H3 (H3K9me3) engages heterochromatin protein 1 (HP1) to drive chromatin compaction and transcriptional silencing. The erasure of this repressive mark and its replacement with acetyl\/acyl groups recruits positive factors such as BRD4\/BET to elicit gene transcription. We report that in Friedreich\u2019s ataxia, a synthetic gene regulator (SynGR1) drives transcription across repressive chromatin\n                  <jats:italic>without<\/jats:italic>\n                  removal or replacement of H3K9me3 or HP1. By selectively recruiting BRD4\/BET into repressive GAA-repeats in frataxin (\n                  <jats:italic>FXN<\/jats:italic>\n                  ), SynGR1 creates a paradoxical state where gene transcription and repressive chromatin co-exist. Contrary to convention, we find that BRD4 readily partitions into phase separated HP1 condensates in vitro and into HP1 puncta in patient-derived cells, thus presenting a mechanistic explanation for desilencing transcription without the dispersal of mesoscale repressive chromatin. Epigenetic drugs that gate sequential steps in transcription, synergistically stimulate\n                  <jats:italic>FXN<\/jats:italic>\n                  expression while concomitantly increasing, rather than eliminating, repressive H3K9me3 and HP1 levels. More broadly, this study highlights the dynamic nature of repressive chromatin and the context-dependence of epigenetic marks in regulating gene expression.\n                <\/jats:p>","DOI":"10.64898\/2026.04.10.717856","type":"posted-content","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T13:10:12Z","timestamp":1776085812000},"source":"Crossref","is-referenced-by-count":0,"title":["BRD4 recruitment desilences transcription without erasure or depletion of repressive chromatin"],"prefix":"10.64898","author":[{"given":"Christopher J.","family":"Brandon","sequence":"first","affiliation":[{"name":"Department of Chemical Biology and Therapeutics, St. Jude Children\u2019s Research Hospital, 262 Danny Thomas Pl., Memphis, TN 38105"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Robinson-Thiewes","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology and Therapeutics, St. Jude Children\u2019s Research Hospital, 262 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