Epigenetics: Losing control

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Age-related dysregulation of the chromatin-remodeling enzyme histone deacetylase 1 (HDAC1) contributes to age-induced loss of remyelination efficiency in mice.

Aging impairs remyelination efficiency, for reasons that are not fully understood. Casaccia-Bonnefil and colleagues now show that oligodendrocyte differentiation during remyelination is regulated by chromatin-remodelling enzymes, and that this control declines with age.

To investigate the regulation of the recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) during remyelination, the authors induced demyelination and subsequent remyelination in the corpus callosum of young mice by exposing them to the toxin cuprizone for 6 weeks. After 2 weeks of treatment, at which time OPCs are thought to be being mobilized to sites of demyelination, the authors observed increased expression of Sox 2, a gene that is involved in maintaining progenitor multipotency. After 4–6 weeks of treatment, as new myelin formation began, SOX2 and other proteins that inhibit OPC differentiation, including HES5, were downregulated and markers of differentiation, such as myelin genes, were upregulated.

How are these changes in gene expression coordinated? The authors observed an increase in the levels of the chromatin-remodelling enzyme histone deacetylase 1 (HDAC1) in OPCs during remyelination and proposed that HDAC activity might control the expression of differentiation regulators. Indeed, chromatin immunoprecipitation showed that binding of HDAC1 to promoter regions of Sox2 and Hes5 decreased after 2 weeks of cuprizone exposure and then increased after 4 weeks. The temporal pattern of promoter occupancy by HDAC1 was mirrored by changes in the levels of histone H3 acetylation in the chromatin of OPCs.

Administering an HDAC inhibitor increased SOX2 and HES5 levels and lowered the expression of myelin genes in the remyelinating corpus callosum. This correlated with a lower percentage of mature oligodendrocytes in comparison to controls. The importance of HDAC activity for OPC differentiation was confirmed by experiments that showed that silencing HDAC using short interfering RNA impairs OPC differentiation in vitro.

To determine whether a dysregulation of HDAC activity contributes to age-induced loss of remyelination efficiency, the authors carried out cuprizone-induced demyelination in 10-month-old mice. When compared with younger mice with comparable levels of axonal damage, the old mice displayed inefficient remyelination and inappropriate expression of myelin genes and transcription factors. The authors also observed lower HDAC1 levels in OPCs of the older mice. Furthermore, HDACs were not recruited to the Sox2 and Hes5 promoters in the cuprizone-treated older mice.

This study indicates that the loss of remyelination efficiency in aging mice involves the loss of epigenetic regulation of oligodendrocyte differentiation. In addition to shedding light on the mechanisms of remyelination control, these findings might point to new therapeutic targets for remyelination disorders such as multiple sclerosis.

Katherine Whalley

References

Shen, S. et al. Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nature Neurosci. 11, 1024–1034 (2008) | Article | PubMed |