Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression

Mol Cell. 2020 Feb 20;77(4):840-856.e5. doi: 10.1016/j.molcel.2019.11.021. Epub 2019 Dec 26.


Polycomb group proteins (PcGs) maintain transcriptional repression to preserve cellular identity in two distinct repressive complexes, PRC1 and PRC2, that modify histones by depositing H2AK119ub1 and H3K27me3, respectively. PRC1 and PRC2 exist in different variants and show a complex regulatory cross-talk. However, the contribution that H2AK119ub1 plays in mediating PcG repressive functions remains largely controversial. Using a fully catalytic inactive RING1B mutant, we demonstrated that H2AK119ub1 deposition is essential to maintain PcG-target gene repression in embryonic stem cells (ESCs). Loss of H2AK119ub1 induced a rapid displacement of PRC2 activity and a loss of H3K27me3 deposition. This preferentially affected PRC2.2 variant with respect to PRC2.1, destabilizing canonical PRC1 activity. Finally, we found that variant PRC1 forms can sense H2AK119ub1 deposition, which contributes to their stabilization specifically at sites where this modification is highly enriched. Overall, our data place H2AK119ub1 deposition as a central hub that mounts PcG repressive machineries to preserve cell transcriptional identity.

Keywords: Chromatin modifications; H2AK119ub1; H3K27me3; JARID2; MTF2; PRC1; PRC2; Polycomb; RING1B; transcriptional repression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chromatin / metabolism
  • Embryonic Stem Cells / metabolism
  • Gene Expression Regulation*
  • Histones / metabolism*
  • Mutation, Missense
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism*
  • Polycomb Repressive Complex 2 / metabolism*
  • Polycomb Repressive Complex 2 / physiology
  • Transcription, Genetic*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination*


  • Chromatin
  • Histones
  • Mtf2 protein, mouse
  • Polycomb Repressive Complex 2
  • Polycomb Repressive Complex 1
  • Rnf2 protein, mouse
  • Ubiquitin-Protein Ligases