@article{c1a78c4037844c5ba285c13f78803638,
title = "NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition",
abstract = "Disruption of antagonism between SWI/SNF chromatin remodelers and polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of the polycomb protein EZH2 was approved for the treatment of a sarcoma mutant in the SWI/SNF subunit SMARCB1, but resistance occurs. Here, we performed CRISPR screens in SMARCB1-mutant rhabdoid tumor cells to identify genetic contributors to SWI/SNF-polycomb antagonism and potential resistance mechanisms. We found that loss of the H3K36 methyltransferase NSD1 caused resistance to EZH2 inhibition. We show that NSD1 antagonizes polycomb via cooperation with SWI/SNF and identify co-occurrence of NSD1 inactivation in SWI/SNF-defective cancers, indicating in vivo relevance. We demonstrate that H3K36me2 itself has an essential role in the activation of polycomb target genes as inhibition of the H3K36me2 demethylase KDM2A restores the efficacy of EZH2 inhibition in SWI/SNF-deficient cells lacking NSD1. Together our data expand the mechanistic understanding of SWI/SNF and polycomb interplay and identify NSD1 as the key for coordinating this transcriptional control.",
keywords = "BAF, EZH2 inhibition, NSD1, SWI/SNF, chromatin, epigenetics, polycomb, transcription",
author = "Yiannis Drosos and Myers, {Jacquelyn A.} and Beisi Xu and Mathias, {Kaeli M.} and Beane, {Emma C.} and Sandi Radko-Juettner and Mobley, {Robert J.} and Larsen, {Margaret E.} and Federica Piccioni and Xiaotu Ma and Jonathan Low and Hansen, {Baranda S.} and Peters, {Samuel T.} and Bhanu, {Natarajan V.} and Dhanda, {Sandeep K.} and Taosheng Chen and Upadhyaya, {Santhosh A.} and Pruett-Miller, {Shondra M.} and Root, {David E.} and Garcia, {Benjamin A.} and Partridge, {Janet F.} and Roberts, {Charles W.M.}",
note = "Funding Information: We thank all members of the Roberts lab for insightful discussions. This work was supported by the National Cancer Institute (NCI) R01 CA113794 and R01 CA172152 to C.W.M.R., R01 CA196539 to B.A.G., CURE AT/RT Now to C.W.M.R., Garrett B. Smith Foundation to C.W.M.R., and St Jude Children{\textquoteright}s Research Hospital Collaborative Research Consortium on Chromatin Regulation in Pediatric Cancer to B.A.G. and C.W.M.R. S.R.-J. is funded by the St Jude Graduate School of Biomedical Sciences and NCI Ruth L. Kirschstein NRSA for Individual Predoctoral Fellows ( F31 CA261150 ). We thank Protein Production Core for Cas9 and Hartwell Center Core for library preparation and sequencing. We also thank St Jude Center for Applied Bioinformatics (CAB) for help with the alignment of RNA-seq and ChIP-seq reads. St Jude cores are supported via Cancer Center support grant ( NCI CCSG 2 P30 CA021765 ) and ALSAC of St Jude Children{\textquoteright}s Research Hospital . Funding Information: We thank all members of the Roberts lab for insightful discussions. This work was supported by the National Cancer Institute (NCI) R01 CA113794 and R01 CA172152 to C.W.M.R. R01 CA196539 to B.A.G. CURE AT/RT Now to C.W.M.R. Garrett B. Smith Foundation to C.W.M.R. and St Jude Children's Research Hospital Collaborative Research Consortium on Chromatin Regulation in Pediatric Cancer to B.A.G. and C.W.M.R. S.R.-J. is funded by the St Jude Graduate School of Biomedical Sciences and NCI Ruth L. Kirschstein NRSA for Individual Predoctoral Fellows (F31 CA261150). We thank Protein Production Core for Cas9 and Hartwell Center Core for library preparation and sequencing. We also thank St Jude Center for Applied Bioinformatics (CAB) for help with the alignment of RNA-seq and ChIP-seq reads. St Jude cores are supported via Cancer Center support grant (NCI CCSG 2 P30 CA021765) and ALSAC of St Jude Children's Research Hospital. Y.D. and C.W.M.R. conceived the experiments and study design. J.A.M. and B.X. performed computational analyses of the data and statistical analyses. Y.D. K.M.M. S.R.-J. E.C.B. and M.E.L. contributed to cell line experiments. Y.D. K.M.M. E.C.B. and M.E.L. contributed to RNA-seq and ChIP-seq experiments. R.J.M. contributed to the generation of G401-SMARCB1 inducible cells. D.E.R. and F.P. contributed to the design, execution, and analysis of the CRISPR GSK126 resistance screen. X.M. contributed to the analysis of patient data and mutations in NSD1/2/3 and SWI/SNF encoding genes. J.L. and T.C. contributed to the design and execution of experiments with standard chemotherapeutics. S.A.U. and S.K.D. analyzed the St Jude ATRT patient data. S.M.P.-M. designed the CRISPR fitness assay and NSD1 CRISPR-edited pooled cells. B.S.H. and S.T.P. contributed to the generation of NSD1 CRISPR-edited pooled cells and the analysis of the CRISPR fitness assay results. B.A.G. and N.V.B. contributed to the analysis of histone PTM MS-analysis. Y.D. J.A.M. B.X. K.M.M. S.R.-J. M.E.L. E.C.B. J.F.P. and C.W.M.R. contributed to the interpretation of experiments. Y.D. J.F.P. and C.W.M.R. wrote the manuscript with input from all co-authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = jul,
day = "7",
doi = "10.1016/j.molcel.2022.04.015",
language = "English",
volume = "82",
pages = "2472--2489.e8",
journal = "Molecular cell",
issn = "1097-2765",
number = "13",
}