title: Interplay between H1 and HMGN epigenetically regulates OLIG1&2 expression and oligodendrocyte differentiation.
abstract: An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not clear. We find that during embryonic stem cell differentiation loss of HMGNs leads to down regulation of genes involved in neural differentiation, and that the transcription factor OLIG2 is a central node in the affected pathway. Loss of HMGNs affects the expression of OLIG2 as well as that of OLIG1, two transcription factors that are crucial for oligodendrocyte lineage specification and nerve myelination. Loss of HMGNs increases the chromatin binding of histone H1, thereby recruiting the histone methyltransferase EZH2 and elevating H3K27me3 levels, thus conferring a repressive epigenetic signature at Olig1&2 sites. Embryonic stem cells lacking HMGNs show reduced ability to differentiate towards the oligodendrocyte lineage, and mice lacking HMGNs show reduced oligodendrocyte count and decreased spinal cord myelination, and display related neurological phenotypes. Thus, the presence of HMGN proteins is required for proper expression of neural differentiation genes during embryonic stem cell differentiation. Specifically, we demonstrate that the dynamic interplay between HMGNs and H1 in chromatin epigenetically regulates the expression of OLIG1&2, thereby affecting oligodendrocyte development and myelination, and mouse behavior.
authors.affiliation: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Deng
authors.affiliation: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Postnikov
authors.affiliation: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Shaofei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.|Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Lillian
authors.initials: L
authors.lastname: Garrett
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.|Institute of Molecular Psychiatry, University of Bonn, 53125 Bonn, Germany.
authors.forename: Ildikó
authors.initials: I
authors.lastname: Rácz
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.|Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.|Technische Universität München-Weihenstephan, Chair of Developmental Genetics c/o Helmholtz Zentrum München, 85764 Neuherberg, Germany.|German Center for Neurodegenerative Diseases (DZNE) Site Munich, Munich Germany.|Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, 80336 Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.|Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85354 Freising, Germany.|German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Martin Hrabe
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bustin
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D024001:HMGN Proteins / Q000502:physiology*; D024241:HMGN1 Protein / Q000235:genetics / Q000502:physiology; D024242:HMGN2 Protein / Q000235:genetics / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D024001:HMGN Proteins; D024241:HMGN1 Protein; D024242:HMGN2 Protein; D006657:Histones; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C494786:Olig1 protein, mouse; C512773:Olig2 protein, mouse; C498410:Ezh2 protein, mouse