USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

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Abstract

Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.

Abstract

Ubiquitin-specific protease 7 regulates histone H2A ubiquitylation and gene repression by the Polycomb system.

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Most cited references 66

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Role of histone H2A ubiquitination in Polycomb silencing.

Hengbin Wang, Liangjun Wang, Hediye Erdjument-Bromage … (2004)

Covalent modification of histones is important in regulating chromatin dynamics and transcription. One example of such modification is ubiquitination, which mainly occurs on histones H2A and H2B. Although recent studies have uncovered the enzymes involved in histone H2B ubiquitination and a 'cross-talk' between H2B ubiquitination and histone methylation, the responsible enzymes and the functions of H2A ubiquitination are unknown. Here we report the purification and functional characterization of an E3 ubiquitin ligase complex that is specific for histone H2A. The complex, termed hPRC1L (human Polycomb repressive complex 1-like), is composed of several Polycomb-group proteins including Ring1, Ring2, Bmi1 and HPH2. hPRC1L monoubiquitinates nucleosomal histone H2A at lysine 119. Reducing the expression of Ring2 results in a dramatic decrease in the level of ubiquitinated H2A in HeLa cells. Chromatin immunoprecipitation analysis demonstrated colocalization of dRing with ubiquitinated H2A at the PRE and promoter regions of the Drosophila Ubx gene in wing imaginal discs. Removal of dRing in SL2 tissue culture cells by RNA interference resulted in loss of H2A ubiquitination concomitant with derepression of Ubx. Thus, our studies identify the H2A ubiquitin ligase, and link H2A ubiquitination to Polycomb silencing.

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Genome Regulation by Polycomb and Trithorax: 70 Years and Counting.

Bernd Schuettengruber, Henri-Marc Bourbon, Luciano Di Croce … (2017)

Polycomb (PcG) and Trithorax (TrxG) group proteins are evolutionarily conserved chromatin-modifying factors originally identified as part of an epigenetic cellular memory system that maintains repressed or active gene expression states. Recently, they have been shown to globally control a plethora of cellular processes. This functional diversity is achieved by their ability to regulate chromatin at multiple levels, ranging from modifying local chromatin structure to orchestrating the three-dimensional organization of the genome. Understanding this system is a fascinating challenge of critical relevance for biology and medicine, since misexpression or mutation of multiple PcG components, as well as of TrxG members of the COMPASS family and of the SWI/SNF complex, is implicated in cancer and other diseases.

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Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation.

Mariana de Napoles, Jacqueline Mermoud, Rika Wakao … (2004)

In many higher organisms, 5%-15% of histone H2A is ubiquitylated at lysine 119 (uH2A). The function of this modification and the factors involved in its establishment, however, are unknown. Here we demonstrate that uH2A occurs on the inactive X chromosome in female mammals and that this correlates with recruitment of Polycomb group (PcG) proteins belonging to Polycomb repressor complex 1 (PRC1). Based on our observations, we tested the role of the PRC1 protein Ring1B and its closely related homolog Ring1A in H2A ubiquitylation. Analysis of Ring1B null embryonic stem (ES) cells revealed extensive depletion of global uH2A levels. On the inactive X chromosome, uH2A was maintained in Ring1A or Ring1B null cells, but not in double knockout cells, demonstrating an overlapping function for these proteins in development. These observations link H2A ubiquitylation, X inactivation, and PRC1 PcG function, suggesting an unanticipated and novel mechanism for chromatin-mediated heritable gene silencing.

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Author and article information

Contributors

Ayestha Sijm:

ORCID: https://orcid.org/0000-0002-7304-9062

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Yaser Atlasi:

ORCID: https://orcid.org/0000-0002-7350-1784

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Project administrationRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Jan A. van der Knaap:

ORCID: https://orcid.org/0000-0002-9175-6086

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing

Joyce Wolf van der Meer:

ORCID: https://orcid.org/0000-0001-6077-8170

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing

Gillian E. Chalkley: Role: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Visualization

Karel Bezstarosti: Role: InvestigationRole: MethodologyRole: Project administration

Dick H. W. Dekkers:

ORCID: https://orcid.org/0000-0001-7057-6257

Role: Investigation

Wouter A. S. Doff:

ORCID: https://orcid.org/0000-0001-9755-6686

Role: Formal analysisRole: SoftwareRole: Visualization

Zeliha Ozgur:

ORCID: https://orcid.org/0000-0002-7171-1884

Role: Investigation

Wilfred F. J. van IJcken:

ORCID: https://orcid.org/0000-0002-0421-8301

Role: Formal analysisRole: InvestigationRole: SoftwareRole: ValidationRole: Writing - review & editing

Jeroen A. A. Demmers:

ORCID: https://orcid.org/0000-0002-8757-9611

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

C. Peter Verrijzer:

ORCID: https://orcid.org/0000-0002-6476-3264

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: November 2022

Publication date (Electronic, pub): 04 November 2022

Volume: 8

Issue: 44

Electronic Location Identifier: eabq7598

Affiliations

[ ¹ ]Department of Biochemistry, Erasmus University Medical Center, Rotterdam, Netherlands.

[ ² ]Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK.

[ ³ ]Proteomics Center, Erasmus University Medical Center, Rotterdam, Netherlands.

[ ⁴ ]Center for Biomics, Erasmus University Medical Center, Rotterdam, Netherlands.

Author notes

[* ]Corresponding author. Email: j.demmers@ 123456erasmusmc.nl (J.A.A.D.); y.atlasi@ 123456qub.ac.uk (Y.A.); c.verrijzer@ 123456erasmusmc.nl (C.P.V.)

[†]

These authors contributed equally to this work and should be considered joint first authors.

[‡]

Lead contact.

Author information

Ayestha Sijm https://orcid.org/0000-0002-7304-9062

Yaser Atlasi https://orcid.org/0000-0002-7350-1784

Jan A. van der Knaap https://orcid.org/0000-0002-9175-6086

Joyce Wolf van der Meer https://orcid.org/0000-0001-6077-8170

Dick H. W. Dekkers https://orcid.org/0000-0001-7057-6257

Wouter A. S. Doff https://orcid.org/0000-0001-9755-6686

Zeliha Ozgur https://orcid.org/0000-0002-7171-1884

Wilfred F. J. van IJcken https://orcid.org/0000-0002-0421-8301

Jeroen A. A. Demmers https://orcid.org/0000-0002-8757-9611

C. Peter Verrijzer https://orcid.org/0000-0002-6476-3264

Article

Publisher ID: abq7598

DOI: 10.1126/sciadv.abq7598

PMC ID: 9635827

PubMed ID: 36332031

SO-VID: bf2b7249-d25b-4ce8-a82d-93fb1a0c8d3c

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 28 April 2022

Date accepted : 16 September 2022

Funding

Funded by: Dutch Research Council ECHO;

Award ID: 711.014.001

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USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

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Most cited references 66

Role of histone H2A ubiquitination in Polycomb silencing.

Genome Regulation by Polycomb and Trithorax: 70 Years and Counting.

Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation.

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Cited by 9

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