Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction

Zijlmans, Dick W.; Talón, Irene; Verhelst, Sigrid; Bendall, Adam; Nerum, Karlien Van; Javali, Alok; Malcolm, Andrew A.; Knippenberg, Sam S. F. A. van; Biggins, Laura; To, San Kit; Janiszewski, Adrian; Admiraal, Danielle; Knops, Ruth; Corthout, Nikky; Balaton, Bradley P.; Georgolopoulos, Grigorios; Panda, Amitesh; Bhanu, Natarajan V.; Collier, Amanda J.; Fabian, Charlene; Allsop, Ryan Nicolaas; Chappell, Joel; Pham, Thi Xuan Ai; Oberhuemer, Michael; Ertekin, Cankat; Vanheer, Lotte; Athanasouli, Paraskevi; Lluı́s, Frederic; Deforce, Dieter; Jansen, Joop H.; García, Benjamin A.; Vermeulen, Michiel; Rivron, Nicolas; Dhaenens, Maarten; Marks, Hendrik; Rugg‐Gunn, Peter J.; Pasque, Vincent

doi:10.1038/s41556-022-00932-w

Cited by 45 publications

(44 citation statements)

References 119 publications

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“…In line with the idea of multi-omics integration ( 99 ), our findings show how multiple chromatin-centered approaches are needed to describe the complexity of biological processes such as DNA damage repair. At the same time the temporal dimension is fundamental for defining the protein dynamics via unbiased approaches like mass spectrometry.…”

Section: Discussionsupporting

confidence: 75%

Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair

Sigismondo

Arseni

Palacio-Escat

et al. 2023

Nucleic Acids Research

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The DNA damage response (DDR) is essential to maintain genome stability, and its deregulation predisposes to carcinogenesis while encompassing attractive targets for cancer therapy. Chromatin governs the DDR via the concerted interplay among different layers, including DNA, histone post-translational modifications (hPTMs) and chromatin-associated proteins. Here, we employ multi-layered proteomics to characterize chromatin-mediated functional interactions of repair proteins, signatures of hPTMs and the DNA-bound proteome during DNA double-strand break (DSB) repair at high temporal resolution. Our data illuminate the dynamics of known and novel DDR-associated factors both at chromatin and at DSBs. We functionally attribute novel chromatin-associated proteins to repair by non-homologous end-joining (NHEJ), homologous recombination (HR) and DSB repair pathway choice. We reveal histone reader ATAD2, microtubule organizer TPX2 and histone methyltransferase G9A as regulators of HR and involved in poly-ADP-ribose polymerase-inhibitor sensitivity. Furthermore, we distinguish hPTMs that are globally induced by DNA damage from those specifically acquired at sites flanking DSBs (γH2AX foci-specific) and profiled their dynamics during the DDR. Integration of complementary chromatin layers implicates G9A-mediated monomethylation of H3K56 in DSBs repair via HR. Our data provide a dynamic chromatin-centered view of the DDR that can be further mined to identify novel mechanistic links and cell vulnerabilities in DSB repair.

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Section: Discussionsupporting

confidence: 75%

Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair

Sigismondo

Arseni

Palacio-Escat

et al. 2023

Nucleic Acids Research

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“…In line with the idea of multi-omics integration (85), our findings show how multiple chromatin-centered approaches are needed to describe the complexity of a biological processes such as DNA damage repair. At the same time the temporal dimension is fundamental for defining the protein dynamics via unbiased approaches like mass spectrometry.…”

Section: Discussionsupporting

confidence: 76%

Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair

Sigismondo

Arseni

Hofmann

et al. 2021

Preprint

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SUMMARYThe DNA damage response (DDR) is essential to maintain genome stability, and its deregulation predisposes to carcinogenesis while encompassing attractive targets for cancer therapy. Chromatin governs the DDR via interplay among all chromatin layers including DNA, histones post-translational modifications (hPTMs), and chromatin-associated proteins. Here we employ multi-layered proteomics to characterize chromatin-mediated interactions of repair proteins, signatures of hPTMs, and the DNA-bound proteome during DNA double-strand break repair at high temporal resolution. We functionally attribute novel chromatin-associated proteins to repair by non-homologous end-joining or homologous recombination (HR) revealing histone reader ATAD2, microtubule organizer TPX2 and histone methyltransferase G9A as regulators of HR and PARP inhibitor sensitivity. Furthermore, we dynamically profile numerous hPTMs at γH2AX-mononucleosomes during the DDR. Integration of these complementary data implicated G9A-mediated monomethylation of H3K56 in HR. Collectively, we provide a dynamic chromatin-centered view of DDR, while representing a valuable resource for the use of PARP inhibitors in cancer. Graphical abstract

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“…Although the studies were conducted using various loss-of-function methods, the picture emerged that embryos could not survive past gastrulation, without the PRC2 core proteins [ 17 , 55 , 56 ]. Recent studies identified an important role for PRC2 in restricting trophoblast induction in human naïve pluripotent stem cells in vitro [ 57 , 58 ], suggesting a role in the earliest mammalian lineage decision after fertilization. In PRC1, the loss of RING1B protein results in developmental arrest at E6.5, during gastrulation, but RING1A mutants were able to survive and reach birth, although displaying defects in transformation of the axial skeleton and altered levels of Hox gene expression [ 59 , 60 ].…”

Section: Roles Of Polycomb Group Proteins In Pluripotency and Early D...mentioning

confidence: 99%

The Role of Polycomb Proteins in Cell Lineage Commitment and Embryonic Development

Loh

Veenstra

2022

Epigenomes

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Embryonic development is a highly intricate and complex process. Different regulatory mechanisms cooperatively dictate the fate of cells as they progress from pluripotent stem cells to terminally differentiated cell types in tissues. A crucial regulator of these processes is the Polycomb Repressive Complex 2 (PRC2). By catalyzing the mono-, di-, and tri-methylation of lysine residues on histone H3 tails (H3K27me3), PRC2 compacts chromatin by cooperating with Polycomb Repressive Complex 1 (PRC1) and represses transcription of target genes. Proteomic and biochemical studies have revealed two variant complexes of PRC2, namely PRC2.1 which consists of the core proteins (EZH2, SUZ12, EED, and RBBP4/7) interacting with one of the Polycomb-like proteins (MTF2, PHF1, PHF19), and EPOP or PALI1/2, and PRC2.2 which contains JARID2 and AEBP2 proteins. MTF2 and JARID2 have been discovered to have crucial roles in directing and recruiting PRC2 to target genes for repression in embryonic stem cells (ESCs). Following these findings, recent work in the field has begun to explore the roles of different PRC2 variant complexes during different stages of embryonic development, by examining molecular phenotypes of PRC2 mutants in both in vitro (2D and 3D differentiation) and in vivo (knock-out mice) assays, analyzed with modern single-cell omics and biochemical assays. In this review, we discuss the latest findings that uncovered the roles of different PRC2 proteins during cell-fate and lineage specification and extrapolate these findings to define a developmental roadmap for different flavors of PRC2 regulation during mammalian embryonic development.

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Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction

Cited by 45 publications

References 119 publications

Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair

Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair

Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair

The Role of Polycomb Proteins in Cell Lineage Commitment and Embryonic Development

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