Epigenome programing by H3.3K27M mutation creates a dependence of pediatric glioma on SMARCA4

Mo, Yan, Duan, Shoufu, Zhang, Xu, Hua, Xu, Zhou, Hui, Wei, Hong-Jian, Watanabe, Jun, McQuillan, Nicholas, Su, Zhenyi, Gu, Wei, Wu, Cheng-Chia, Vakoc, Christopher R, Hashizume, Rintaro, Chang, Kenneth, Zhang, Zhiguo (October 2022) Epigenome programing by H3.3K27M mutation creates a dependence of pediatric glioma on SMARCA4. Cancer Discovery. CD-21. ISSN 2159-8274

Abstract

Patients with diffuse midline gliomas-H3K27-altered (DMG) display a dismal prognosis. However, the molecular mechanisms underlying DMG tumorigenesis remain poorly defined. Here we show that SMARCA4, the catalytic subunit of mammalian SWI/SNF chromatin remodeling complex, is essential for the proliferation, migration and invasion of DMG cells and tumor growth in patient-derived DMG xenograft models. SMARCA4 co-localizes with SOX10 at gene regulatory elements (GRE) to control the expression of genes involved in cell growth and extracellular matrix (ECM). Moreover, SMARCA4 chromatin binding is reduced upon depletion of SOX10 or H3.3K27M, a mutation occurring in about 60% DMG tumors. Furthermore, the SMARCA4 occupancy at enhancers marked by both SOX10 and H3K27 acetylation is reduced the most upon depleting the H3.3K27M mutation. Taken together, our results support a model in which epigenome reprogramming by H3.3K27M creates a dependence on SMARCA4-mediated chromatin remodeling to drive gene expression and the pathogenesis of H3.3K27M DMG.

Item Type:	Paper
Subjects:	diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromatin remodeling bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
CSHL Authors:	Vakoc, Christopher R. Chang, Kenneth
Communities:	CSHL labs > Chang lab CSHL labs > Vakoc lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	28 October 2022
Date Deposited:	07 Nov 2022 21:49
Last Modified:	07 Nov 2022 21:49
URI:	https://repository.cshl.edu/id/eprint/40747

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