Dnmt3a-Dependent Nonpromoter DNA Methylation Facilitates Transcription of Neurogenic Genes

Abstract

DNA methylation at proximal promoters facilitates lineage restriction by silencing cell type–specific genes. However, euchromatic DNA methylation frequently occurs in regions outside promoters. The functions of such nonproximal promoter DNA methylation are unclear. Here we show that the de novo DNA methyltransferase Dnmt3a is expressed in postnatal neural stem cells (NSCs) and is required for neurogenesis. Genome-wide analysis of postnatal NSCs indicates that Dnmt3a occupies and methylates intergenic regions and gene bodies flanking proximal promoters of a large cohort of transcriptionally permissive genes, many of which encode regulators of neurogenesis. Surprisingly, Dnmt3a-dependent nonproximal promoter methylation promotes expression of these neurogenic genes by functionally antagonizing Polycomb repression. Thus, nonpromoter DNA methylation by Dnmt3a may be used for maintaining active chromatin states of genes critical for development.

Epigenetic regulation of aging stem cells

“…This review will focus primarily on changes in histone modifications. However, we also note that regulators of DNA methylation are required for the function of a variety of adult stem cells (Zhao et al, 2003;Ma et al, 2009;Trowbridge et al, 2009;Sen et al, 2010;Trowbridge and Orkin, 2010;Wu et al, 2010), and that they complex with chromatin modifiers to elicit changes in chromatin state (Jones et al, 1998;Nan et al, 1998;Fuks et al, 2003). In addition, chromatin remodeling factors are also important for stem and progenitor cell function (Lessard et al, 2007;Ho et al, 2009;Ho and Crabtree, 2010), suggesting that several epigenetic mechanisms could coordinately control adult stem cell gene expression programs during organismal aging.…”

“…In mice, deletion of the DNA methyltransferase 3a (Dnmt3a) causes a defect in neuronal differentiation of postnatal NSCs. Genome-wide mapping of DNMT3A binding and H3K27me3 in NSCs reveals that loss of DNMT3A binding results in an increase in H3K27me3 levels and a decrease in the expression of genes critical for promoting neuronal differentiation (Wu et al, 2010). Moreover, the DNA-methylating activity of DNMT3A is required for the inhibition of PcG binding at neuronal genes (Wu et al, 2010).…”

“…Genome-wide mapping of DNMT3A binding and H3K27me3 in NSCs reveals that loss of DNMT3A binding results in an increase in H3K27me3 levels and a decrease in the expression of genes critical for promoting neuronal differentiation (Wu et al, 2010). Moreover, the DNA-methylating activity of DNMT3A is required for the inhibition of PcG binding at neuronal genes (Wu et al, 2010). Interestingly, EZH2 has been shown to recruit DNA methyltransferases to promote de novo DNA methylation (Vire et al, 2006), suggesting that EZH2 may be critical for promoting neuronal differentiation of NSCs by initiating the attenuation of its own repression of differentiation-specific genes.…”

Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms

“…5mCs can also be located within non-promoter intra-and intergenic sequences, and DNA repeat sequences [40]. In contrast to promoter 5mC, the presence of 5mC in intragenic regions (the gene body) can be correlated positively with gene expression [41].…”

The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

“…Thus, different modifications on different residues, the same modification on different residues, and the abundance of a single modified residue may all have unique effects on transcription. In addition to histones, DNA itself can be modified by methylation on cytosine residues, a mark that has generally been correlated with gene silencing (Bachman et al, 2003;Fuks et al, 2000), but may also facilitate transcription in certain contexts (Wu et al, 2010).…”