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Here, we report that the repressive euchromatic H3K9me2 histone mark, deposited by the histone methyltransferases EHMT1 and EHMT2 enzymes, increases in proliferating OPCs in mice following optogenetic stimulation of neuronal activity. Using primary cultured OPCs with genetic deletion of <jats:italic>Ehmt1<\/jats:italic> and <jats:italic>Ehmt2<\/jats:italic>, and pharmacological inhibition of EHMT enzymatic activity, we reveal the importance of these enzymes in repressing the expression of genes regulating cell death and electrical properties in proliferating OPCs. Consistent with these findings, we detect higher levels of cholinergic muscarinic receptors, fewer numbers of oligodendrocyte lineage cells, and lower levels of the myelin basic protein (MBP) in mice with lineage\u2010specific ablation of <jats:italic>Ehmt1<\/jats:italic> and <jats:italic>Ehmt2<\/jats:italic>. Together these data suggest that the repressive H3K9me2 histone mark, whose levels increase in proliferating OPCs after neuronal stimulation, is an important modulator of cell death and proteins regulating the electrical properties of OPCs.<\/jats:p>","DOI":"10.1002\/glia.70014","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T21:25:54Z","timestamp":1743197154000},"page":"1420-1436","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Histone Methyltransferases <scp>EHMT1<\/scp> and <scp>EHMT2<\/scp> Repress the Expression of Genes Related to Excitability and Cell Death in Oligodendrocyte Progenitors"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0844-7731","authenticated-orcid":false,"given":"Mathilde","family":"Pruvost","sequence":"first","affiliation":[{"name":"Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hye\u2010Jin","family":"Park","sequence":"additional","affiliation":[{"name":"Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chlo\u00e9","family":"Habermacher","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Li","sequence":"additional","affiliation":[{"name":"Norris Medical Library University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Cecilia","family":"Angulo","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266  Paris France"},{"name":"GHU PARIS Psychiatrie et Neurosciences  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6274-2710","authenticated-orcid":false,"given":"Jia","family":"Liu","sequence":"additional","affiliation":[{"name":"Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4785-9264","authenticated-orcid":false,"given":"Patrizia","family":"Casaccia","sequence":"additional","affiliation":[{"name":"Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York  New York New York USA"},{"name":"Graduate Program in Biology The\u00a0Graduate Center of the City University of New York  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.344218.120"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bht309"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(90)90091-S"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/361258a0"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18984-7"},{"key":"e_1_2_9_7_1","unstructured":"Benchling.2024.\u201cCloud\u2010Based Platform for Biotech R&D|Benchling.\u201dhttps:\/\/www.benchling.com."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a020453"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6000-09.2010"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2023.05.007"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2410"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","DOI":"10.1083\/jcb.202308064","article-title":"Histone H4 Acetylation Differentially Modulates Proliferation in Adult Oligodendrocyte Progenitors","volume":"223","author":"Dansu D. 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