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PMID: 19160500 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency.

Nature neuroscience ·Vol. 11 ·No. 9 ·2008-09-00 ·Pages 1024-34

Shen S, Sandoval J, Swiss VA, Li J, Dupree J, Franklin RJ, Casaccia-Bonnefil P

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.

MeSH Terms
Aging/physiology Animals Animals, Newborn Antigens, CD/metabolism Antigens, Differentiation, Myelomonocytic/metabolism Cell Differentiation/drug effects,physiology Cells, Cultured Cerebral Cortex/cytology Cuprizone Demyelinating Diseases/chemically induced,drug therapy,pathology,physiopathology Disease Models, Animal Enzyme Inhibitors/administration & dosage Epigenesis, Genetic/drug effects,genetics,physiology Glial Fibrillary Acidic Protein/metabolism Histone Deacetylases/genetics,metabolism Mice Mice, Inbred C57BL Microglia/drug effects,ultrastructure Microscopy, Electron, Transmission/methods Myelin Proteins/genetics,metabolism Neurosecretory Systems/drug effects,pathology Rats Regeneration/drug effects,physiology Stem Cells/drug effects,physiology Time Factors Transcription Factors/genetics,metabolism Transcription, Genetic Valproic Acid/pharmacology
Chemicals
Antigens, CD Antigens, Differentiation, Myelomonocytic CD68 antigen, human Enzyme Inhibitors Glial Fibrillary Acidic Protein Myelin Proteins Transcription Factors Cuprizone Valproic Acid Histone Deacetylases histone deacetylase 3
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Shen Siming
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA.
Sandoval Juan
Swiss Victoria A
Li Jiadong
Dupree Jeff
Franklin Robin J M
Casaccia-Bonnefil Patrizia
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/nn.2172
Published
2008-09-00
Pages
1024-34
Language
English
Region
United States
NLM ID
9809671
PMCID
PMC2656679
Subset
IM
Grants
NINDS NIH HHS · NS52738 · United States
NINDS NIH HHS · R01 NS052738-03 · United States
NINDS NIH HHS · R01 NS042925 · United States
NINDS NIH HHS · NS042925 · United States
NINDS NIH HHS · R37 NS042925 · United States
NINDS NIH HHS · R01 NS042925-06 · United States
NINDS NIH HHS · R01 NS052738 · United States
Corrections
CommentIn
PMID: 18725899
External Links
PubMed source DOI: 10.1038/nn.2172 PMC Full Text View journal details
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