@article{a2123ca590c04b4d8052a3745a3466e3,
title = "The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma",
abstract = "Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations. Incorporation of the synovial sarcoma SS18-SSX fusion into BAF complexes results in concomitant eviction of BAF47. McBride et al. show that SS18-SSX retargets BAF complexes from enhancers to polycomb domains to oppose PRC2-mediated repression. Reincorporation of BAF47 upon suppression of SS18-SSX restores enhancer activation but is not required for proliferative arrest.",
keywords = "ATP-dependent chromatin remodeling, SWI/SNF (BAF) complexes, bivalency, chromatin, enhancers, fusion oncoprotein, pediatric cancer, polycomb, synovial sarcoma",
author = "McBride, {Matthew J.} and Pulice, {John L.} and Beird, {Hannah C.} and Ingram, {Davis R.} and D'Avino, {Andrew R.} and Shern, {Jack F.} and Charville, {Gregory W.} and Hornick, {Jason L.} and Nakayama, {Robert T.} and Garcia-Rivera, {Enrique M.} and Araujo, {Dejka M.} and Wang, {Wei Lien} and Tsai, {Jen Wei} and Michelle Yeagley and Wagner, {Andrew J.} and Futreal, {P. Andrew} and Javed Khan and Lazar, {Alexander J.} and Cigall Kadoch",
note = "Funding Information: We are grateful to members of the Kadoch and Lazar laboratories for helpful experimental advice and guidance. We thank A. Kuo and G.R. Crabtree for the BAF155 (SMARCC1) homemade polyclonal antibody used in these studies. We thank Zach Herbert and members of the Molecular Biology Core Facility (MBCF) for library preparation and sequencing, and J. Buenrostro (Broad Institute) for guidance in ATAC-seq experiments. This work was supported in part by awards from the NIH DP2 New Innovator Award 1DP2CA195762-01 (to C.K.), the American Cancer Society Research Scholar Award RSG-14-051-01-DMC (to C.K.), the Pew-Stewart Scholars in Cancer Research Grant (to C.K.), the Alex's Lemonade Stand Foundation Young Investigator Award (to C.K.), and a generous gift from the Sill Family (to C.K.). In addition, this work was supported in part by NIH grant number 5 T32 GM095450-04 (to M.J.M.), and by the Harvard University Graduate School of Arts and Sciences (GSAS) Fellowship (to M.J.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the NIH. Funding Information: We are grateful to members of the Kadoch and Lazar laboratories for helpful experimental advice and guidance. We thank A. Kuo and G.R. Crabtree for the BAF155 (SMARCC1) homemade polyclonal antibody used in these studies. We thank Zach Herbert and members of the Molecular Biology Core Facility (MBCF) for library preparation and sequencing, and J. Buenrostro (Broad Institute) for guidance in ATAC-seq experiments. This work was supported in part by awards from the NIH DP2 New Innovator Award 1DP2CA195762-01 (to C.K.), the American Cancer Society Research Scholar Award RSG-14-051-01-DMC (to C.K.), the Pew-Stewart Scholars in Cancer Research Grant (to C.K.), the Alex's Lemonade Stand Foundation Young Investigator Award (to C.K.), and a generous gift from the Sill Family (to C.K.). In addition, this work was supported in part by NIH grant number 5 T32 GM095450-04 (to M.J.M.), and by the Harvard University Graduate School of Arts and Sciences (GSAS) Fellowship (to M.J.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the NIH. Publisher Copyright: {\textcopyright} 2018",
year = "2018",
month = jun,
day = "11",
doi = "10.1016/j.ccell.2018.05.002",
language = "English",
volume = "33",
pages = "1128--1141.e7",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}
