The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies.

Details

Ressource 1Download: e202000808.full.pdf (5311.31 [Ko])
State: Public
Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_6ADA64868153
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies.
Journal
Life science alliance
Author(s)
Boulay G., Cironi L., Garcia S.P., Rengarajan S., Xing Y.H., Lee L., Awad M.E., Naigles B., Iyer S., Broye L.C., Keskin T., Cauderay A., Fusco C., Letovanec I., Chebib I., Nielsen P.G., Tercier S., Cherix S., Nguyen-Ngoc T., Cote G., Choy E., Provero P., Suvà M.L., Rivera M.N., Stamenkovic I., Riggi N.
ISSN
2575-1077 (Electronic)
ISSN-L
2575-1077
Publication state
Published
Issued date
02/2021
Peer-reviewed
Oui
Volume
4
Number
2
Pages
e202000808
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene SS18 to one of three SSX genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose polycomb repressor complex (PRC) 2 activity, while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and are associated with vulnerability to USP7 loss, a core member of ncPRC1.1. Using the power of primary tumor organoids, our work helps define the mechanisms of epigenetic dysregulation on which SyS cells are dependent.
Pubmed
Web of science
Open Access
Yes
Create date
04/01/2021 12:03
Last modification date
08/05/2021 6:32
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