Synergy between Variant PRC1 Complexes Defines Polycomb-Mediated Gene Repression

Summary

The 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.

Graphical Abstract

Highlights

• •

  Canonical PRC1 complexes contribute little to H2AK119ub1 and gene repression

• •

  Variant PRC1 complexes deposit H2AK119ub1 broadly throughout the genome

• •

  Pervasive deposition of H2AK119ub1 by PCGF3/5-PRC1 is linked to X chromosome silencing

• •

  Synergy between variant PRC1 complexes defines Polycomb-mediated gene repression

Abstract

In this article, Fursova et al. uncover the central determinants of Polycomb-mediated gene repression in ESCs. They demonstrate that deposition of H2AK119ub1 and gene repression is driven by synergy between variant PRC1 complexes with little contribution from canonical PRC1 complexes, which mediate higher-order chromatin structures.