Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes

Abstract

BackgroundDNA methylation and the Polycomb repression system are epigenetic mechanisms that play important roles in maintaining transcriptional repression. Recent evidence suggests that DNA methylation can attenuate the binding of Polycomb protein components to chromatin and thus plays a role in determining their genomic targeting. However, whether this role of DNA methylation is important in the context of transcriptional regulation is unclear.ResultsBy genome-wide mapping of the Polycomb Repressive Complex 2-signature histone mark, H3K27me3, in severely DNA hypomethylated mouse somatic cells, we show that hypomethylation leads to widespread H3K27me3 redistribution, in a manner that reflects the local DNA methylation status in wild-type cells. Unexpectedly, we observe striking loss of H3K27me3 and Polycomb Repressive Complex 2 from Polycomb target gene promoters in DNA hypomethylated cells, including Hox gene clusters. Importantly, we show that many of these genes become ectopically expressed in DNA hypomethylated cells, consistent with loss of Polycomb-mediated repression.ConclusionsAn intact DNA methylome is required for appropriate Polycomb-mediated gene repression by constraining Polycomb Repressive Complex 2 targeting. These observations identify a previously unappreciated role for DNA methylation in gene regulation and therefore influence our understanding of how this epigenetic mechanism contributes to normal development and disease.

Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation

“…Thus, loss of Polycomb recruitment coincides with increased susceptibility to DNA methylation. This finding is compatible with the observation of increased H3K27 methylation upon global loss of DNA methylation (23,24,33,34), which we also observe in our genome-wide datasets (Fig. S7A).…”

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

“…Altered methylation of the proximal-1 promoter region of StAR is crucial for regulating its expression (45)(46)(47) and conserved across species (48). Because H3K27me3 is an established transcriptional repressor (49)(50)(51), including of StAR (47), we investigated if the level of H3K27me3 upstream of the coding region of StAR was altered using a ChIP assay (47,51).…”

“…To investigate a potential mechanism for reduced expression of StAR, we hypothesized that it was because of histone modifications in its proximal-1 promoter region, which are important in its regulation (45)(46)(47). Using ChIP, we showed that H3K27me3 upstream of the coding region of StAR, which is associated with transcriptional repression (47,(49)(50)(51), was increased in testes of DBP-exposed rats. Consistent with this finding, we found increased immunoexpression of H3K27me3 in adult Leydig cells of DBP-exposed rats and their stem cells in fetal life.…”

The molecular underpinnings of totipotency

“…Hence, an alternative interpretation is that Polycomb maintains pluripotency by restricting totipotency or extraembryonic gene transcription. It has recently been shown that, in cells exhibiting global hypomethylation, Polycomb complexes can be titrated away from promoters to bind to intergenic regions [62]. The net effect of this would be the de-repression of extraembryonic promoters normally bound by Polycomb complexes, allowing the upregulation of trophoblast and PE genes.…”