Targeting SAGA/ATAC complexes disrupts chromatin regulation and cholesterol metabolism in diffuse midline glioma

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 in vitro and prolongs survival in xenograft models. Small molecule inhibitors targeting SAGA/ATAC-associated histone acetylation, ubiquitination, and methylation similarly suppress DMG growth. Integrative chromatin and transcriptomic profiling reveals that disruption of SAGA/ATAC through SGF29 knockout remodels the DMG chromatin landscape, producing distinct alterations at metabolic genes (loss of H3K9ac) and at embryonic/neurodevelopmental genes (redistribution of H3K4me3 and H3K27me3) and accompanying transcriptional changes. We further show that inhibition of the SAGA/ATAC-associated KAT2A/2B histone acetyltransferases represses cholesterol metabolism gene expression and that combined KAT2A/2B and cholesterol synthesis inhibition synergistically suppresses DMG growth in vitro and in a xenograft model. Together, these findings establish a mechanistic link between SAGA/ATAC-dependent chromatin regulation and the transcriptional and metabolic dysregulation underlying DMG malignancy.