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

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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.

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Figure 1: Complex temporal pattern of regulation of gene expression in the corpus callosum of cuprizone-treated mice.
Figure 2: The pattern of histone acetylation in oligodendrocyte progenitors in the corpus callosum of cuprizone-treated mice correlates with the expression profile of the stem cell marker Sox2 and of the differentiation inhibitor Hes5.
Figure 3: Systemic administration of HDAC inhibitors to cuprizone-treated mice increases histone acetylation on the promoters of Sox2 and Hes5 and prevents oligodendrocytic differentiation.
Figure 4: The impaired remyelination detected in VPA-treated mice is not dependent on axonal damage.
Figure 5: Impaired recovery of myelin gene expression in old mice correlates with decreased number of HDAC+ cells and increased number of Sox2+ immature cells.
Figure 6: The pattern of microglial and astrocytic gene expression is similar in the corpus callosum of young and old mice after cuprizone treatment.
Figure 7: Age-dependent and dose-independent recruitment of repressive complexes containing HDAC to Hes5 and Sox2 promoters during remyelination.
Figure 8: Selective class I HDAC isoforms are necessary for oligodendrocyte progenitor differentiation and Sox2 downregulation.

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Acknowledgements

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.

Author information

S.S. and J.S. performed the majority of the experiments and data analysis. J.L. contributed to the in vivo experiments and V.A.S. to the silencing experiments. J.D. performed the ultrastructural analysis. R.J.M.F. contributed to the initial phase of the project and helped with text writing and editing. P.C.-B. was responsible for planning the experiments, supervising the project, critically analyzing the results and writing the manuscript.

Correspondence to Patrizia Casaccia-Bonnefil.

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Shen, S., Sandoval, J., Swiss, V. et al. Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci 11, 1024–1034 (2008) doi:10.1038/nn.2172

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