Targeting SAGA/ATAC disrupts chromatin regulation and cholesterol metabolism in diffuse midline glioma [CUT&Run]

ABSTRACT: Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors characterized by chromatin and transcriptional dysregulation induced by H3K27M mutations with a median survival of 11-15 months. We identified multiple components of the SAGA and ATAC chromatin regulatory complexes as DMG genetic dependencies and found that genetic or pharmacological inhibition of the SAGA/ATAC-associated chromatin reader SGF29 reduces DMG proliferation. Small molecules targeting SAGA/ATAC-associated histone acetylation, ubiquitination, and methylation similarly suppress DMG growth. Chromatin profiling and RNA‑seq analyses reveal that SGF29 regulates H3K9ac and H3K4me3 deposition at both H3K27M‑bound and H3K27M‑independent loci controlling proliferation, differentiation, and metabolic programs. We further show that inhibition of the SAGA/ATAC histone acetyltransferases KAT2A/2B reduces DMG viability by repressing cholesterol‑metabolism gene expression, and that combined cholesterol‑pathway and KAT2A/2B inhibition synergistically suppresses DMG growth in vitro and decreases proliferation in a xenograft model. Together, these findings define a functional link between SAGA/ATAC‑dependent chromatin modulation and transcriptional and metabolic dysregulation underlying DMG malignancy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318286 | GEO | 2026/02/05

REPOSITORIES: GEO