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PRMT5 inhibition by LLY-283 in HSJD-DIPG-007 DMG cells

ABSTRACT: PRMT5 inhibition by LLY-283 in HSJD-DIPG-007 DMG cells

PROVIDER: PRJNA957302 | ENA |

REPOSITORIES: ENA

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Project description:Diffuse intrinsic pontine glioma (DIPG) is a uniformly lethal brainstem tumor of childhood, driven by mutations in histone H3 at lysine 27 (K27M) leading to altered epigenetic regulation. Epigenomic analyses of DIPG have shown global loss of repressive chromatin marks accompanied by DNA hypomethylation. However, studies providing a static view of the epigenome do not adequately capture the regulatory underpinnings of DIPG intratumoral heterogeneity and phenotypic plasticity. To address this, we performed whole-genome bisulfite sequencing (WGBS) on 23 primary patient DIPG specimens, 4 patient-derived DIPG neurosphere cell lines, and 5 normal controls and applied a novel framework for analysis of DNA methylation variability, permitting the derivation of comprehensive genome-wide DNA methylation potential energy landscapes that capture intrinsic epigenetic variation. We show that DIPG exhibits a markedly disordered epigenome, with increasingly stochastic DNA methylation localizing to key regulatory elements and genes. We demonstrate marked epigenetic instability at genes regulating pluripotency and developmental identity, potentially enabling cells to sample a diverse range of transcriptional programs and differentiation states. We then evaluated the responsiveness of the DIPG epigenetic landscape to pharmacologic modulation. Treatment with the DNA hypomethylating agent decitabine produced profound genome-wide demethylation and reduced DNA methylation stochasticity at active enhancers, bivalent promoters, and promoters of key developmental genes. Decitabine treatment elicited changes in gene expression, including upregulation of immune signaling, and sensitized DIPG cells to the effects of histone deacetylase inhibition. This study provides a resource for dissecting the epigenetic instability that underlies DIPG heterogeneity and plasticity, suggesting the application of epigenetic therapies to constrain the range of epigenetic states available to DIPG cells.

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PRMT5 inhibition by LLY-283 in HSJD-DIPG-007 DMG cells

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