Journal
NATURE NEUROSCIENCE
Volume 11, Issue 9, Pages 1024-1034Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2172
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Funding
- US National Institutes of Health National Institute of Neurological Disorders and Stroke [NS042925, NS52738]
- National Multiple Sclerosis Society [NMSS RG-3957]
- MS Research Foundation
- Research into Ageing
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS042925, R37NS042925, R01NS052738] Funding Source: NIH RePORTER
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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.
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