title: Chromatin landscape defined by repressive histone methylation during oligodendrocyte differentiation.
abstract: In many cell types, differentiation requires an interplay between extrinsic signals and transcriptional changes mediated by repressive and activating histone modifications. Oligodendrocyte progenitors (OPCs) are electrically responsive cells receiving synaptic input. The differentiation of these cells into myelinating oligodendrocytes is characterized by temporal waves of gene repression followed by activation of myelin genes and progressive decline of electrical responsiveness. In this study, we used chromatin isolated from rat OPCs and immature oligodendrocytes, to characterize the genome-wide distribution of the repressive histone marks, H3K9me3 and H3K27me3, during differentiation. Although both marks were present at the OPC stage, only H3K9me3 marks (but not H3K27me3) were found to be increased during differentiation, at genes related to neuronal lineage and regulation of membrane excitability. Consistent with these findings, the levels and activity of H3K9 methyltransferases (H3K9 HMT), but not H3K27 HMT, increased more prominently upon exposure to oligodendrocyte differentiating stimuli and were detected in stage-specific repressive protein complexes containing the transcription factors SOX10 or YY1. Silencing H3K9 HMT, but not H3K27 HMT, impaired oligodendrocyte differentiation and functionally altered the response of oligodendrocytes to electrical stimulation. Together, these results identify repressive H3K9 methylation as critical for gene repression during oligodendrocyte differentiation.
authors.affiliation: Department of Neuroscience.
authors.forename: Jia
authors.identifier: http://orcid.org/0000-0002-6457-2935
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neuroscience.
authors.forename: Laura
authors.initials: L
authors.lastname: Magri
authors.affiliation: Bioinformatics Laboratory, Department of Medicine, and.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience.
authors.forename: Nidaa O
authors.identifier: http://orcid.org/0000-0003-2420-7295
authors.initials: NO
authors.lastname: Marsh
authors.affiliation: Institute of Neuropathology, University Hospital Münster, D-48149 Münster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Albrecht
authors.affiliation: Department of Neuroscience, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Jimmy L
authors.initials: JL
authors.lastname: Huynh
authors.affiliation: Department of Neuroscience.
authors.forename: Jasbir
authors.identifier: http://orcid.org/0000-0001-6842-2240
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Institute of Neuropathology, University Hospital Münster, D-48149 Münster, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.affiliation: Bioinformatics Laboratory, Department of Medicine, and.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Slesinger
authors.affiliation: Department of Neuroscience, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and patrizia.casaccia@mssm.edu.
authors.forename: Patrizia
authors.identifier: http://orcid.org/0000-0002-4785-9264
authors.initials: P
authors.lastname: Casaccia
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation / Q000379:methods; D005260:Female; D006657:Histones / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism*; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002843:Chromatin; D006657:Histones
keywords: ChIP-seq; epigenetics; myelin; potassium channel