Epigenetic mechanisms facilitating oligodendrocyte development, maturation, and aging

Abstract

The process of oligodendrocyte differentiation is regulated by a dynamic interaction between a genetic and an epigenetic program. Recent studies, addressing nucleosomal histone modifications have considerably increased our knowledge regarding epigenetic regulation of gene expression during oligodendrocyte development and aging. These results have generated new hypotheses regarding the mechanisms underlying the decreased efficiency of endogenous remyelination in response to demyelinating injuries with increasing age. In this review, we present an overview of the epigenetic mechanisms regulating gene expression at specific stages of oligodendrocyte differentiation and maturation as well as the changes that occur with aging.

Figure 1

Histone modification. A. Model of the basic transcriptional unit, a nucleosome, shows the histone core octamer (2x H2A, H2B, H3, and H4, in blue) and the H1 linker protein, enwrapped 1.5 times by 150 bp of DNA (red). The histone tails can be modified by enzymes that catalyze methylation, acetylation, phosphorylation, citrullination, ubiquitination or sumoylation of specific amino acids. B. The scheme of 3 nucleosomes depicts a part of the chromatin with promotor and gene DNA that is open for transcription. The transcriptional active state is achieved by the acetylation or methylation of lysine 9 (K9) or lysine 4 (K4) respectively in the tail of histone 3 (H3). C. Transcriptional silencing can be caused by the histone modification resulting from the methylation of K9 or trimethylation of K27.

Figure 2

Histone modification and oligodendrocyte development. A. The differentiation of neural stem cells into oligodendrocyte precursor cells (OPCs) requires the recruitment of class I histone deacetylases, HDACs ( in particular 1 & 2) at genes encoding transcriptional inhibitors of OPC formation (e.g. Hes5, Id2, Id4, Sox11, and Tcf4) and those encoding the fate towards neurons or astrocytes. The HDAC activity at lysine 9 (K9) of histone protein 3 (H3) leads to the silencing of the expression of these genes, enabling oligodendrocyte formation. Yin Yang 1 and presumably Ezh2 are thought to facilitate the recruitment of the HDACs at these specific locations. The repression is still reversible, since some regulation is required to prevent premature myelination B. Essential stable repression of inhibitors of myelin genes at the mature stage of the oligodendrocyte, is established via the action of histone methyl transferases, HMTs (in particular of the Suvar3-9 family) resulting in the methylation of H3K9, followed by the binding of HP1 (histone protein 1) causing compaction of the nucleosome. The stable silencing of the myelin gene inhibitors promote myelination activity. C. The remyelination capacity of OPCs in aged animals is reduced due to diminished recruitment of HDACs and HMTs, resulting in histone acetyl transferase (HAT) activity to prevail causing an acetylated, transcriptional activated state of genes blocking proper OPC development and maturation and myelination.