Promoter bivalency favors an open chromatin architecture in embryonic stem cells

Abstract

In embryonic stem cells (ESCs), developmental gene promoters are characterized by their bivalent chromatin state, with simultaneous modification by MLL2 and Polycomb complexes. Although essential for embryogenesis, bivalency is functionally not well understood. Here, we show that MLL2 plays a central role in ESC genome organization. We generate a catalog of bona fide bivalent genes in ESCs and demonstrate that loss of MLL2 leads to increased Polycomb occupancy. Consequently, promoters lose accessibility, long-range interactions are redistributed, and ESCs fail to differentiate. We pose that bivalency balances accessibility and long-range connectivity of promoters, allowing developmental gene expression to be properly modulated.

Nucleoporin 153 links nuclear pore complex to chromatin architecture by mediating CTCF and cohesin binding atcis-regulatory elements and TAD boundaries

“…Regulation of bivalent gene expression has been proposed to be necessary for maintenance of ES cell pluripotency 1,8 . Bivalent state is established through the simultaneous catalytic activity of MLL and Polycomb Repressive Complex 2 (PRC2).…”

“…Polycomb binding coupled with loss of chromatin accessibility across the promoters and alterations in long-range chromatin interactions 8 . These results suggest that maintenance of bivalent state might be causally linked to higher order chromatin organization during regulation of developmental gene expression.…”

“…Nuclear pore complex; nucleoporin; chromatin structure; transcription; chromatin architecture; nuclear structure INTRODUCTION Establishment of cell lineage specification, maintenance of cellular states and cellular responses to developmental cues rely on gene regulation and spatial genome organization during development 1,2,3 . Emerging data point to highly coordinated activity between epigenetic mechanisms that involve nuclear architecture, chromatin structure and chromatin organization 4,5,6,7,8 . However, our understanding on how nuclear architectural proteins are causally linked to chromatin organization and impact gene regulation have been limited underscoring the importance of defining the molecular determinants.…”

“…NUP153 depletion results in differential gene expression that is most prevalent at bivalent genes 8 . To determine the mechanism by which NUP153 regulates CTCF and cohesin function during gene expression, we utilized IEGs, including Egr1, c-Fos and Jun loci, which we identified as NUP153 targets in mouse ES cells.…”

Quantitative multiplexed ChIP reveals global alterations that shape promoter bivalency in ground state embryonic stem cells

“…Our data suggests that high H3K4me3 at bivalent genes is a molecular manifestation of the serum-primed state. Indeed, a recent report suggests that H3K4me3 specifies the robust and timely induction of bivalent promoters during differentiation 25 . Given that H3K27me3 is per se dispensable for ground state pluripotency 5,16 , we hypothesize that low H3K4me3 together with high H3K27me3 levels at bivalent promoters act to safeguard the ground state of pluripotency.…”