Epigenetic regulation of stem cells differentiating along the neural lineage

Many lineage-specific genes are poised and silenced in stem cells. Upon differentiation, genes that are related to self-renewal and alternative lineages are stably silenced. CpG methylation at proximal promoters and PRC2-mediated H3K27me3 play a role in silencing genes temporarily or permanently, with or without coexistence of active epigenetic marks, respectively. Interestingly, DNA methylation on neuronal genes that is distal to transcription start site enable transcription activation owing to its ability to repel PRC2-mediated inhibition. In addition, DNA demethylase Tet proteins play a role in regulation of changes in DNA methylation and related H3K27me3 during differentiation. Collectively, a complex epigenetic network formed by H3K4me3, histone acetylation/deacetylation, H3K27me3 and DNA methylation/demethylation act together to regulate stem cell self-renewal and differentiation.

► DNA methylation is a dynamic gene regulatory mechanism that sets up a pluripotent state at the early stages of development. ► DNA methylation may play a role in both gene inhibition and activation. ► Tets may regulate DNA methylation during development and establish a pluripotent epigenetic state during early embryogenesis. ► Through non-proximal promoter methylation Dnmt3a activates transcription of neurogenic genes in neural stem cells by antagonizing PcG mediated repression. ► Distal-promoter DNA methylation ensures tissue-specific gene regulation.