Synergy between Variant PRC1 Complexes Defines Polycomb-Mediated Gene Repression.

Nadezda A Fursova,Haruhiko Koseki,Neil P Blackledge,Robert J Klose,Manabu Nakayama,Anca M Farcas,Shinsuke Ito,Yoko Koseki,Hamish W King

doi:10.1016/j.molcel.2019.03.024

Abstract

SummaryThe Polycomb system modifies chromatin and plays an essential role in repressing gene expression to control normal mammalian development. However, the components and mechanisms that define how Polycomb protein complexes achieve this remain enigmatic. Here, we use combinatorial genetic perturbation coupled with quantitative genomics to discover the central determinants of Polycomb-mediated gene repression in mouse embryonic stem cells. We demonstrate that canonical Polycomb repressive complex 1 (PRC1), which mediates higher-order chromatin structures, contributes little to gene repression. Instead, we uncover an unexpectedly high degree of synergy between variant PRC1 complexes, which is fundamental to gene repression. We further demonstrate that variant PRC1 complexes are responsible for distinct pools of H2A monoubiquitylation that are associated with repression of Polycomb target genes and silencing during X chromosome inactivation. Together, these discoveries reveal a new variant PRC1-dependent logic for Polycomb-mediated gene repression.

Highlights

In multicellular organisms, the specification and maintenance of highly defined gene expression patterns is required for tissue organization and normal development
We discover that variant Polycomb repressive complex 1 (PRC1) complexes play a fundamental and synergistic role in shaping genomic H2AK119ub1, supporting communication between PRC1 and PRC2 to form Polycomb chromatin domains, and defining gene repression
In cells, canonical PRC1 function is linked to the formation of higher-order chromatin interactions, which rely on PHC proteins but appear to occur independently of H2AK119ub1 (Boettiger et al, 2016; Eskeland et al, 2010; Francis et al, 2004; Kundu et al, 2017; Lau et al, 2017; Lavigne et al, 2004; Wani et al, 2016)

Summary

Introduction

The specification and maintenance of highly defined gene expression patterns is required for tissue organization and normal development. In addition to these DNA-encoded mechanisms, it has become clear that the chromatin template on which transcription occurs can profoundly regulate gene expression, during development. This often relies on mobilization of nucleosomes by chromatin remodeling enzymes and post-translational modification of histones to create chromatin states that can potentiate or inhibit transcription (Atlasi and Stunnenberg, 2017; Lai and Pugh, 2017). Polycomb systems function at gene-regulatory sites, where their activities inhibit the expression of associated genes (reviewed in Blackledge et al, 2015; Di Croce and Helin, 2013; Schuettengruber et al, 2017)

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