Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4

Yan Mo, Shoufu Duan, Xu Zhang, Xu Hua, Hui Zhou, Hong Jian Wei, Jun Watanabe, Nicholas McQuillan, Zhenyi Su, Wei Gu, Cheng Chia Wu, Christopher R. Vakoc, Rintaro Hashizume, Kenneth Chang, Zhiguo Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Patients with diffuse midline gliomas that are H3K27 altered (DMG) display a dis-mal prognosis. However, the molecular mechanisms underlying DMG tumorigenesis remain poorly defined. Here we show that SMARCA4, the catalytic subunit of the 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 colocalizes with SOX10 at gene regulatory elements to control the expression of genes involved in cell growth and the 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. SIGNIFICANCE: DMG is a deadly pediatric glioma currently without effective treatments. We discov-ered that the chromatin remodeler SMARCA4 is essential for the proliferation of DMG with H3K27M mutation in vitro and in vivo, identifying a potentially novel therapeutic approach to this disease.

Original languageEnglish (US)
Pages (from-to)2906-2929
Number of pages24
JournalCancer discovery
Issue number12
StatePublished - Dec 1 2022

ASJC Scopus subject areas

  • Oncology


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