A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells

Abstract

The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed "bivalent domains," consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.

Application of machine learning methods to histone methylation ChIP-Seq data reveals H4R3me2 globally represses gene expression

“…The highest impact activating multivalent term is also bivalent and composed of an activating mark, H3K4me2, and a repressive mark, H3R2me1. Thus, at the bivalent level, the linear model terms suggest that there is significant overlap between opposing marks (i.e., activating and repressive) and that one of them tends to "override" the other, similar to the observation that H3K27me3 overrides H3K4me3 in ES cells [10,12]. …”

“…Using ChIP-chip and ChIP-Seq, bivalent domains of H3K4me3 and H3K27me3 were observed at genes encoding developmentally important transcription factors in embryonic stem cells [10-12]. It is suggested that these genes are transcriptionally silent but poised for activation during development.…”

Ube2s regulates Sox2 stability and mouse ES cell maintenance

“…2,3,25,[48][49][50] However, knowledge regarding the precise mechanisms underlying how Sox2 is posttranslationally regulated remains limited. Several studies have shown that the protein activity of Sox2 can be modified by sumoylation, methylation, acetylation and phosphorylation.…”

Beyond early development: Xenopus as an emerging model for the study of regenerative mechanisms

“…In embryonic stem cells, it has been shown that many silent loci coding for developmental genes are associated with nucleosomes containing not only the inhibitory trimethyl lysine 27 mark on Histone H3 (me 3 K27 H3) but also the trimethyl lysine 4 Histone H3 (me 3 K4 H3) mark, which normally indicates active loci. Therefore, it has been proposed that this bivalent histone code poises the developmental genes for later activation during the differentiation process (Bernstein et al, 2006). Scott Stewart, from the Izpisuá -Belmonte lab at the Salk Institute presented some intriguing results at a recent meeting showing that this bivalent histone code is also present in the intact nonregenerating fin of the zebrafish (Scott Stewart and J.C.I.B., unpublished observations).…”