PR‐DUB safeguards Polycomb repression through H2AK119ub1 restriction

Polycomb group (PcG) proteins are critical chromatin regulators for cell fate control. The mono‐ubiquitylation on histone H2AK119 (H2AK119ub1) is one of the well‐recognized mechanisms for Polycomb repressive complex 1 (PRC1)‐mediated transcription repression. Unexpectedly, the specific H2AK119 deubiquitylation complex composed by additional sex comb‐like proteins and BAP1 has also been genetically characterized as Polycomb repressive deubiquitnase (PR‐DUB) for unclear reasons. However, it remains a mystery whether and how PR‐DUB deficiency affects chromatin states and cell fates through impaired PcG silencing. Here through a careful epigenomic analysis, we demonstrate that a bulk of H2AK119ub1 is diffusely distributed away from promoter regions and their enrichment is positively correlated with PRC1 occupancy. Upon deletion of Asxl2 in mouse embryonic stem cells (ESCs), a pervasive gain of H2AK119ub1 is coincident with increased PRC1 sampling at chromatin. Accordingly, PRC1 is significantly lost from a subset of highly occupied promoters, leading to impaired silencing of associated genes before and after lineage differentiation of Asxl2‐null ESCs. Therefore, our study highlights the importance of genome‐wide H2AK119ub1 restriction by PR‐DUB in safeguarding robust PRC1 deposition and its roles in developmental regulation.