Epigenetic Rewiring Underlies SMARCA4-Dependent Maintenance of Progenitor State in Pediatric H3K27M Diffuse Midline Glioma

Abstract

Epigenetic reprogramming drives tumorigenesis in pediatric H3K27M diffuse midline glioma (DMG) by altering the canonical functions of chromatin remodeling complexes. These studies (i) identified BRG1 (encoded by SMARCA4), the catalytic subunit of the mammalian SWI/SNF (BAF) chromatin remodeling complex, as a novel dependency in pediatric H3K27M glioma; (ii) investigated the molecular mechanisms underlying the maintenance of the progenitor state; and (iii) demonstrated efficacy for BRG1 inhibitors.The authors identified the BRG1 ATPase as a dependency in pediatric H3K27M-mutant DMG. SOX10 recruits BRG1 to regulatory elements to drive progression. Pharmacologically targeting BRG1 reduced tumor volume and improved survival in vivo. Inhibiting BRG1 ATPase represents a potential therapeutic strategy for pediatric H3K27M DMG. See related article by Panditharatna et al., p. 2880 (5) See related article by Mo et al., p. 2906 (4) .

Figure 1.. Molecular mechanism and treatment strategy for pediatric H3K27M diffuse midline glioma.

A. H3.3K27M rewires the epigenome to create novel dependencies on epigenetic regulators. The transcription factor SOX10 recruits BRG1 to gene regulatory elements that drive expression of extracellular matrix and cell proliferation genes. B. Targeting BRG1 ATPase activity with either ATPase inhibitors or PROTACs shifts cells from a highly proliferative oligodendrocyte precursor-like state to a more differentiated astrocyte-like state, resulting in decreased proliferation and increased apoptosis. Figure created with BioRender.com.