Elongin B orchestrates chromatin and transcriptional programs in H3K27M-mutant diffuse midline glioma

  • bioRxiv. 2026 May 19:2026.05.16.724973. doi: 10.64898/2026.05.16.724973.
Alan L Jiao  1  2 ,  Rebecca L Murdaugh  3  4  5  6 ,  Adam F Kebede  2  7 ,  Claudia A Mimoso  8  9 ,  Barry M Zee  2  10 ,  Rosemary U Richard  3  4  5  6 ,  Kwanha Yu  3  4 ,  Caitlin L Bagnetto  3  4  5  6 ,  Karen Adelman  8  11 ,  Mariella G Filbin  7  11 ,  Yang Shi  1  2 ,  Jamie N Anastas  3  4  5  6
Affiliations
  • 1. Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 2. Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 3. Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
  • 4. The Center for Cell and Gene Therapy (CAGT) and the Stem Cells and Regenerative Medicine Center (StAR), Baylor College of Medicine, Houston, TX, USA.
  • 5. The Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 6. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 7. Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
  • 8. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
  • 9. Department of Genetics, Yale School of Medicine, New Haven, CT USA.
  • 10. Cell Signaling Technology Inc., Danvers, MA, USA.
  • 11. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
PMID: 42239282 DOI: 10.64898/2026.05.16.724973
Abstract

Recurrent driver mutations in genes encoding histone H3 (H3.3K27M and H3.1K27M) are observed in ~80% of diffuse midline gliomas (DMG), which lead to aberrant gene regulation, yet the specific RNA polymerase II (Pol2) regulators that induce transcriptional dysregulation in DMG are not fully defined. 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 KO alters H3K27me3 and H3K27M incorporation at thousands of genomic regions, implicating ELOB in the maintenance of dysfunctional chromatin states in DMG. Correspondingly, PRO-seq and RNA-seq profiling reveal that ELOB loss disrupts Pol2 transcriptional activity and alters the expression of transcripts involved in metabolism, proliferation, and brain development. These findings suggest that Pol2 elongation factors like ELOB cooperate with H3K27M oncohistones to maintain the epigenetic and transcriptional landscape driving DMG malignancy.

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