Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency.
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.
Shen
Siming
S
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA.
Sandoval
Juan
J
Swiss
Victoria A
VA
Li
Jiadong
J
Dupree
Jeff
J
Franklin
Robin J M
RJ
Casaccia-Bonnefil
Patrizia
P
D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009490:Neurosecretory Systems / Q000187:drug effects / Q000473:pathology; D051381:Rats; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014635:Valproic Acid / Q000494:pharmacology; D000099186:Histone Deacetylase 3; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D003471:Cuprizone; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D006655:Histone Deacetylases; D009185:Myelin Proteins; D014157:Transcription Factors; D014635:Valproic Acid; D000099186:Histone Deacetylase 3; C067980:CD68 antigen, human; D000097382:CD68 Molecule