Article abstract
Nature Neuroscience 11, 1024 - 1034 (2008)
Published online: 24 August 2008 | doi:10.1038/nn.2172
Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency
Siming Shen1,5, Juan Sandoval1,5, Victoria A Swiss1, Jiadong Li1, Jeff Dupree2, Robin J M Franklin3 & Patrizia Casaccia-Bonnefil1,4
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.
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA.
- Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Box 980709, Richmond, Virginia 23298, USA.
- Cambridge Centre for Brain Repair and Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
- Present address: Department of Neuroscience and Genetics and Genomics, Mount Sinai School of Medicine, One Gustave Levy Place Box 1065, New York, New York 10029, USA.
- These authors contributed equally to this work.
Correspondence to: Patrizia Casaccia-Bonnefil1,4 e-mail: patrizia.casaccia@mssm.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Epigenetic control of myelin repairNature Neuroscience News and Views (01 Sep 2008)
Neuroscience An ageing view of myelin repairNature News and Views (25 Sep 2008)
See all 13 matches for News And ViewsRESEARCH
Identification of IGFBP-6 as an effector of the tumor suppressor activity of SEMA3BOncogene Original Article
A functional role for EGFR signaling in myelination and remyelinationNature Neuroscience Article (01 Aug 2007)
See all 48 matches for Research
