Multi-omics characterization of the USP7 regulatory circuitry reveals control of H2AK119ub1 dosage uncoupled from H3K27me3 .

ABSTRACT: Ubiquitin-specific protease 7 (USP7) has been implicated in multiple cellular and developmental pathways. However, its molecular network remains poorly defined. We combined quantitative proteomics, transcriptomics and epigenomics to define the core USP7 regulome. We found that USP7 forms a regulatory hub, linking processes involved in the packaging, maintenance and expression of the genome. Further analysis revealed that USP7 regulates non-canonical Polycomb repressive complexes 1 (ncPRC1s) but affects neither canonical PRC1s nor PRC2s. By stabilizing key subunits of PRC1.6 and to a lesser extend PRC1.1, USP7 acts as a rheostat that modulates the global level of H2AK119ub11. Unexpectedly, changes in the genomic deposition of H2AK119ub11 are uncoupled from H3K27me3, challenging prevalent models for Polycomb repression. Indeed, a complete loss of PRC1 and H2AK119ub1 has only a highly restricted effect on H3K27me3. Besides defining the organizational principles of the USP7 regulome, our results reveal selective control of H2AK119ub1 dosage that is disconnected from H3K27me3.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Jeroen Demmers  

LAB HEAD: Jeroen Demmers

PROVIDER: PXD030707 | Pride | 2023-03-11

REPOSITORIES: Pride