BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

Laubscher, Dominik, Gryder, Berkley E, Sunkel, Benjamin D, Andresson, Thorkell, Wachtel, Marco, Das, Sudipto, Roschitzki, Bernd, Wolski, Witold, Wu, Xiaoli S, Chou, Hsien-Chao, Song, Young K, Wang, Chaoyu, Wei, Jun S, Wang, Meng, Wen, Xinyu, Ngo, Quy Ai, Marques, Joana G, Vakoc, Christopher R, Schäfer, Beat W, Stanton, Benjamin Z, Khan, Javed (November 2021) BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma. Nature Communications, 12 (1). p. 6924. ISSN 2041-1723

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Abstract

Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state while blocking terminal differentiation. Here, we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define the mSWI/SNF functional repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes localize to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes, which is recapitulated by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > differentiation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > helicase bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogenes organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types diseases & disorders > cancer > cancer types > rhabdomyosarcoma bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor diseases & disorders > cancer > cancer types
CSHL Authors:	Wu, Xiaoli Vakoc, Christopher R.
Communities:	CSHL labs > Vakoc lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	26 November 2021
Date Deposited:	06 Dec 2021 16:40
Last Modified:	13 Feb 2024 18:42
PMCID:	PMC8626462
URI:	https://repository.cshl.edu/id/eprint/40440

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