SAGA/ATAC complexes sustain aberrant chromatin regulation and promote tumorigenesis in diffuse midline glioma

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors driven by H3K27M mutations affecting chromatin regulation.
• Current therapeutic strategies for DMG are limited, highlighting the need for novel approaches targeting epigenetic dysregulation.

Purpose of the Study:

• To identify genetic dependencies and therapeutic targets within chromatin regulatory complexes in DMG.
• To investigate the role of SGF29 and SAGA/ATAC complexes in DMG pathogenesis and explore combination therapies.

Main Methods:

• Genetic screening to identify DMG dependencies within SAGA and ATAC complexes.
• Pharmacological inhibition of SGF29 and related epigenetic modifiers.
• Chromatin profiling (ChIP-seq) and RNA sequencing (RNA-seq) to analyze gene expression and epigenetic dynamics.
• In vitro studies evaluating drug synergy, including cholesterol metabolism inhibitors.

Main Results:

• SGF29, a component of SAGA/ATAC complexes, was identified as a DMG genetic dependency.
• Inhibition of SGF29 or SAGA/ATAC complexes suppressed DMG proliferation by modulating H3K9ac and H3K4me3 dynamics.
• SAGA/ATAC inhibition repressed genes involved in cholesterol metabolism, and combined inhibition with cholesterol-targeting drugs showed synergistic effects on DMG growth.

Conclusions:

• SGF29 and SAGA/ATAC complexes are critical for DMG proliferation and survival.
• Targeting SAGA/ATAC-dependent chromatin modulation and cholesterol metabolism presents a promising therapeutic strategy for diffuse midline gliomas.
• Combined therapies targeting epigenetic regulators and metabolic pathways may overcome treatment resistance in DMG.