{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T05:49:44Z","timestamp":1792907384153,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,22]]},"group-title":"Neuroscience","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Mental Health","award":["R01 MH116900"],"award-info":[{"award-number":["R01 MH116900"]}]},{"name":"National Institute of Mental Health","award":["F32 MH140478"],"award-info":[{"award-number":["F32 MH140478"]}]},{"name":"National Institute of Mental Health","award":["F32 MH126534"],"award-info":[{"award-number":["F32 MH126534"]}]},{"name":"National Institute of Mental Health","award":["K01 MH139990"],"award-info":[{"award-number":["K01 MH139990"]}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["R21 NS130319"],"award-info":[{"award-number":["R21 NS130319"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["F31 NS132558"],"award-info":[{"award-number":["F31 NS132558"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["F99 NS139541"],"award-info":[{"award-number":["F99 NS139541"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes of Health","award":["F30 AG090096"],"award-info":[{"award-number":["F30 AG090096"]}]},{"name":"National Institute on Drug Abuse","award":["T32ADA007135"],"award-info":[{"award-number":["T32ADA007135"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03a63f080","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Howard Hughes Medical Institute","id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Cindy Silvian Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Histone H3 Gln 5 serotonylation (H3Q5ser) is a recently identified epigenetic modification in brain that modulates\n                  <jats:italic>reader<\/jats:italic>\n                  interactions with adjacent H3 Lys 4 trimethylation (H3K4me3) to promote transcriptional permissiveness\n                  <jats:sup>1,2<\/jats:sup>\n                  . However, whether H3K4me3Q5ser and its associated binding proteins regulate neurodevelopmental gene expression programs remains unknown. Here, we identified the catalytically inactive Lysine methyltransferase 2E (KMT2E) as a\n                  <jats:italic>reader<\/jats:italic>\n                  of combinatorial H3K4me3Q5ser. KMT2E preferentially binds H3K4me3Q5ser over H3K4me3 alone, and enriches at broad chromatin domains marking actively transcribed neurodevelopmental loci. Notably, heterozygous variants in\n                  <jats:italic>KMT2E<\/jats:italic>\n                  have been implicated in ODLURO syndrome, a recently characterized neurodevelopmental disorder (NDD)\n                  <jats:sup>3,4<\/jats:sup>\n                  . To identify the molecular mechanisms underlying ODLURO syndrome, we generated a\n                  <jats:italic>Kmt2e<\/jats:italic>\n                  transgenic mouse model that reproduces behavioral, physiological, and cellular endophenotypes associated with this and other NDDs. Furthermore, we observed that KMT2E mediates these effects by recruiting the NCoR\/HDAC3 repressor complex to H3K4me3Q5ser-marked loci to restrict spreading of co-localized H3 Lys 9 acetylation (H3K9ac). Inhibition of aberrant H3K9ac spreading was sufficient to rescue transcriptional dysregulation in\n                  <jats:italic>Kmt2e<\/jats:italic>\n                  haploinsufficient neurons. These findings thus establish KMT2E as a critical reader of H3 serotonylation during neurodevelopment and provide mechanistic insights into the pathogenesis of ODLURO syndrome.\n                <\/jats:p>","DOI":"10.64898\/2026.09.20.752984","type":"posted-content","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:40:21Z","timestamp":1790106021000},"source":"Crossref","is-referenced-by-count":1,"title":["KMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics"],"prefix":"10.64898","author":[{"given":"Jennifer C","family":"O\u2019Chan","sequence":"first","affiliation":[{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin H.","family":"Weekley","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, School of Medicine at Tsinghua University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohini","family":"Dutta","sequence":"additional","affiliation":[{"name":"Nash Family Department 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