TY - JOUR
T1 - Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency
AU - Shen, Siming
AU - Sandoval, Juan
AU - Swiss, Victoria A.
AU - Li, Jiadong
AU - Dupree, Jeff
AU - Franklin, Robin J.M.
AU - Casaccia-Bonnefil, Patrizia
N1 - Funding Information:
This work was supported by grants from US National Institutes of Health National Institute of Neurological Disorders and Stroke (NS042925 and NS52738 to P.C.-B.), the National Multiple Sclerosis Society (NMSS RG-3957 P.C.-B.), the MS Research Foundation (to P.C.-B.) and Research into Ageing (to R.J.M.F.). We thank J. Williamson for superb assistance with electron microscopy and acknowledge C. Ghiani (University of California Los Angeles) for the gift of the microglial BV-2 cell line.
PY - 2008/9
Y1 - 2008/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=50249167673&partnerID=8YFLogxK
U2 - 10.1038/nn.2172
DO - 10.1038/nn.2172
M3 - Article
C2 - 19160500
AN - SCOPUS:50249167673
SN - 1097-6256
VL - 11
SP - 1024
EP - 1034
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 9
ER -