Abstract
The efficiency of remyelination decreases with age, but the molecular mechanisms responsible for this decline remain only partially understood. In this study, we show that remyelination is regulated by age-dependent epigenetic control of gene expression. In demyelinated young brains, new myelin synthesis is preceded by downregulation of oligodendrocyte differentiation inhibitors and neural stem cell markers, and this is associated with recruitment of histone deacetylases (HDACs) to promoter regions. In demyelinated old brains, HDAC recruitment is inefficient, and this allows the accumulation of transcriptional inhibitors and prevents the subsequent surge in myelin gene expression. Defective remyelination can be recapitulated in vivo in mice receiving systemic administration of pharmacological HDAC inhibitors during cuprizone treatment and is consistent with in vitro results showing defective differentiation of oligodendrocyte progenitors after silencing specific HDAC isoforms. Thus, we suggest that inefficient epigenetic modulation of the oligodendrocyte differentiation program contributes to the age-dependent decline in remyelination efficiency.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / physiology*
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Animals
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Animals, Newborn
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Antigens, CD / metabolism
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Antigens, Differentiation, Myelomonocytic / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cells, Cultured
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Cerebral Cortex / cytology
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Cuprizone
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Demyelinating Diseases / chemically induced
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Demyelinating Diseases / drug therapy
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Demyelinating Diseases / pathology
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Demyelinating Diseases / physiopathology*
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Disease Models, Animal
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Enzyme Inhibitors / administration & dosage
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Epigenesis, Genetic / drug effects
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Epigenesis, Genetic / genetics*
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Epigenesis, Genetic / physiology*
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Glial Fibrillary Acidic Protein / metabolism
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Mice
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Mice, Inbred C57BL
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Microglia / drug effects
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Microglia / ultrastructure
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Microscopy, Electron, Transmission / methods
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Myelin Proteins / genetics
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Myelin Proteins / metabolism*
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Neurosecretory Systems / drug effects
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Neurosecretory Systems / pathology
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Rats
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Regeneration / drug effects
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Regeneration / physiology*
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Stem Cells / drug effects
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Stem Cells / physiology
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic
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Valproic Acid / pharmacology
Substances
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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CD68 antigen, human
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Enzyme Inhibitors
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Glial Fibrillary Acidic Protein
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Myelin Proteins
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Transcription Factors
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Cuprizone
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Valproic Acid
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Histone Deacetylases
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histone deacetylase 3