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

• Published in: Nature neuroscience Vol. 11; no. 9; pp. 1024 - 1034
• Main Authors: Casaccia-Bonnefil, Patrizia, Shen, Siming, Sandoval, Juan, Swiss, Victoria A, Li, Jiadong, Dupree, Jeff, Franklin, Robin J M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2008; Nature Publishing Group
• Subjects: Age; Aging; Aging - physiology; Animal Genetics and Genomics; Animals; Animals, Newborn; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Cerebral Cortex - cytology; Control; Cuprizone; Demyelinating diseases; Demyelinating Diseases - chemically induced; Demyelinating Diseases - drug therapy; Demyelinating Diseases - pathology; Demyelinating Diseases - physiopathology; Disease Models, Animal; Drug therapy; Enzyme Inhibitors - administration & dosage; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - genetics; Epigenesis, Genetic - physiology; Epigenetics; Gene expression; Genetic aspects; Glial Fibrillary Acidic Protein - metabolism; Growth factors; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Mice; Mice, Inbred C57BL; Microglia - drug effects; Microglia - ultrastructure; Microscopy, Electron, Transmission - methods; Multiple sclerosis; Myelin Proteins - genetics; Myelin Proteins - metabolism; Myelin sheath; Neurobiology; Neurosciences; Neurosecretory Systems - drug effects; Neurosecretory Systems - pathology; Physiological aspects; Rats; Regeneration - drug effects; Regeneration - physiology; Stem Cells - drug effects; Stem Cells - physiology; Time Factors; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Valproic Acid - pharmacology; United States; New York; United States > US; Virginia
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2172

With aging comes a decline in remyelination efficiency, but it is currently unknown why this occurs. In this study, the authors reveal an age-dependent epigenetic mechanism that modulates the levels of oligodendrocyte differentiation inhibitors and dictates the extent of remyelination. 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.