Role for Dpy-30 in ES Cell-Fate Specification by Regulation of H3K4 Methylation within Bivalent Domains

Abstract

Summary Histone H3K4 methylation is associated with active genes and, along with H3K27 methylation, is part of a bivalent chromatin mark that typifies poised developmental genes in embryonic stem cells (ESCs). However, its functional roles in ESC maintenance and differentiation are not established. Here we show that mammalian Dpy-30, a core subunit of the SET1/MLL histone methyltransferase complexes, modulates H3K4 methylation in vitro, and directly regulates chromosomal H3K4 trimethylation (H3K4me3) throughout the mammalian genome. Depletion of Dpy-30 does not affect ESC self-renewal, but significantly alters the differentiation potential of ESCs, particularly along the neural lineage. The differentiation defect is accompanied by defects in gene induction and in H3K4 methylation at key developmental loci. Our results strongly indicate an essential functional role for Dpy-30 and SET1/MLL complex-mediated H3K4 methylation, as a component of the bivalent mark, at developmental genes during the ESC fate transitions.

The Trithorax Group Protein Ash2l Is Essential for Pluripotency and Maintaining Open Chromatin in Embryonic Stem Cells

“…Analysis of our Ash2l ChIP-seq data and previously published studies has revealed genome-wide co-occupancy of Ash2l, Rbbp5, Dpy-30, as well as histone H3K4me3 on ES cell chromatin (55,61). These observations underscore their importance for establishing and maintaining an open chromatin in ES cells, and are consistent with Ash2l/Rbbp5/Dpy-30 forming a core complex that is required for establishing and maintaining H3K4me3 (37,61).…”

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

“…Interestingly, Wdr5, a shared component of the Kat8-containing complex and the MLL complex catalyzing H3K4 methylation [56], displays a phenotype similar to that of Kat8 when depleted in ESCs [57]. Given that Dpy30, another MLL complex component regulating H3K4 methylation, is dispensable for ESC self-renewal [58], it seems likely that the Kat8-containing complex mediates the Wdr5 function. In support of this notion, the recruitment of Wdr5 to its target loci, including key pluripotency genes, depends on Kat8 [25].…”

“…Enzymes depositing or removing H3K4 methylation have been shown to play important roles in ESCs. Dpy30, a component of the MLL histone methyltransferase (HMT) complex, is required for ESCs to commit to the neural lineage [58], indicating that H3K4me3 deposited by MLL is crucial for maintaining differentiation potential in ESCs. Deficiency in Kdm1a, an H3K4me2/1-specific demethylase, results in spontaneous differentiation of human ESCs [68].…”

Structure of the SPRY domain of human Ash2L and its interactions with RbBP5 and DPY30

“…The interaction between Ash2L and RbBP5 is essential for MLL1 complex integrity and activity regulation [2,5]. The Ash2L-DPY30 interaction was recently reported to be important for the regulation of nucleosomal H3K4 trimethylation and the differentiation potential of embryonic stem cells [6]. Ash2L protein adopts a modular configuration.…”