Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain.
Timely differentiation of progenitor cells is critical for development. In this study we asked whether global epigenetic mechanisms regulate timing of progenitor cell differentiation into myelin-forming oligodendrocytes in vivo. Histone deacetylation was essential during a specific temporal window of development and was dependent on the enzymatic activity of histone deacetylases, whose expression was detected in the developing corpus callosum. During the first 10 postnatal days, administration of valproic acid (VPA), the specific inhibitor for histone deacetylase activity, resulted in significant hypomyelination with delayed expression of late differentiation markers and retained expression of progenitor markers. Differentiation resumed in VPA-injected rats if a recovery period was allowed. Administration of VPA after myelination onset had no effect on myelin gene expression and was consistent with changes of nucleosomal histones from reversible deacetylation to more stable methylation and chromatin compaction. Together, these data identify global modifications of nucleosomal histones critical for timing of oligodendrocyte differentiation and myelination in the developing corpus callosum.
Shen
Siming
S
Department of Neuroscience and Cell Biology, R. Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Li
Jiadong
J
Casaccia-Bonnefil
Patrizia
P
D000107:Acetylation; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D009186:Myelin Sheath / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology
D015415:Biomarkers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009707:Nucleosomes; D014635:Valproic Acid; D006655:Histone Deacetylases