Elongin B orchestrates chromatin and transcriptional programs in H3K27M‑mutant diffuse midline glioma [XIII_ELOB_CUTandRUN]

We identified multiple regulators of Pol2 elongation as DMG genetic dependencies in a chromatin-focused CRISPR screen. Additional studies confirm that knockout (KO) of the Pol2 SIII complex gene Elongin B (ELOB) inhibits DMG cell proliferation in tissue culture and tumor growth in xenograft models.

Further genomic analyses reveal that ELOB binding sites are enriched in H3K27M oncohistones and that ELOB knockout alters H3K27me3 and H3K27M incorporation at thousands of genomic regions, suggesting a role for ELOB in maintaining dysfunctional chromatin states in DMG. Correspondingly, ELOB loss disrupts Pol2 transcriptional activity and alters the expression of transcripts involved in metabolism, proliferation, and brain development.