RT Journal Article
SR Electronic
T1 The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000808
DO 10.26508/lsa.202000808
VO 4
IS 2
A1 Gaylor Boulay
A1 Luisa Cironi
A1 Sara P Garcia
A1 Shruthi Rengarajan
A1 Yu-Hang Xing
A1 Lukuo Lee
A1 Mary E Awad
A1 Beverly Naigles
A1 Sowmya Iyer
A1 Liliane C Broye
A1 Tugba Keskin
A1 Alexandra Cauderay
A1 Carlo Fusco
A1 Igor Letovanec
A1 Ivan Chebib
A1 Petur Gunnalugur Nielsen
A1 Stéphane Tercier
A1 Stéphane Cherix
A1 Tu Nguyen-Ngoc
A1 Gregory Cote
A1 Edwin Choy
A1 Paolo Provero
A1 Mario L Suvà
A1 Miguel N Rivera
A1 Ivan Stamenkovic
A1 Nicolò Riggi
YR 2021
UL https://www.life-science-alliance.org/content/4/2/e202000808.abstract
AB 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.