title: c-Myc-dependent transcriptional regulation of cell cycle and nucleosomal histones during oligodendrocyte differentiation.
abstract: Oligodendrocyte progenitor cells (OPCs) have the ability to divide or to growth arrest and differentiate into myelinating oligodendrocytes in the developing brain. Due to their high number and the persistence of their proliferative capacity in the adult brain, OPCs are being studied as potential targets for myelin repair and also as a potential source of brain tumors. This study addresses the molecular mechanisms regulating the transcriptional changes occurring at the critical transition between proliferation and cell cycle exit in cultured OPCs. Using bioinformatic analysis of existing datasets, we identified c-Myc as a key transcriptional regulator of this transition and confirmed direct binding of this transcription factor to identified target genes using chromatin immunoprecipitation. The expression of c-Myc was elevated in proliferating OPCs, where it also bound to the promoter of genes involved in cell cycle regulation (i.e. Cdc2) or chromosome organization (i.e. H2afz). Silencing of c-Myc was associated with decreased histone acetylation at target gene promoters and consequent decrease of gene transcripts. c-Myc silencing also induced a global increase of repressive histone methylation and premature peripheral nuclear chromatin compaction while promoting the progression towards differentiation. We conclude that c-Myc is an important modulator of the transition between proliferation and differentiation of OPCs, although its decrease is not sufficient to induce progression into a myelinating phenotype.
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, United States.
authors: L
authors: L
authors: Magri
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, United States.
authors: M
authors: M
authors: Gacias
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, United States.
authors: M
authors: M
authors: Wu
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, United States.
authors: V A
authors: VA
authors: Swiss
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, United States.
authors: W G
authors: WG
authors: Janssen
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, United States; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, United States. Electronic address: patrizia.casaccia@mssm.edu.
authors: P
authors: P
authors: Casaccia
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006657:Histones / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009707:Nucleosomes / Q000235:genetics; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D006657:Histones; D009707:Nucleosomes; D016271:Proto-Oncogene Proteins c-myc
keywords: CNS; development; epigenetic; glioma; histone variant; myelin