Journal
MOLECULAR CELL
Volume 76, Issue 6, Pages 965-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.08.030
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Funding
- Alex's Lemonade Stand Foundation
- McKenna Claire Foundation
- Unravel Pediatric Cancer
- Michael Mosier Defeat DIPG Foundation
- ChadTough Foundation
- N8 Foundation
- Cure Starts Now Foundation
- DIPG Collaborative
- Sam Jeffers Foundation
- Abbie's Army Foundation
- Maiy's Miracle Foundation
- Virginia and D.K. Ludwig Fund for Cancer Research
- National Institute of Neurological Disorders and Stroke [R01NS092597]
- National Institutes of Health (NIH) Director's Common Fund [DP1NS111132]
- Liwei Wang Research Fund
- Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases
- Dr. Mildred Scheel Cancer Foundation [57406718]
- Musella Foundation
- Piedmont Community
- Kisses for Kayla
- LilaBean Foundation
- Pediatric Brain Tumor Atlas-CBTTC
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Development of effective targeted cancer therapies is fundamentally limited by our molecular understanding of disease pathogenesis. Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique substitution to methionine in histone H3 at lysine 27 (H3K27M) that results in globally altered epigenetic marks and oncogenic transcription. Through primary DIPG tumor characterization and isogenic oncohistone expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending upon both the variant of histone H3 and the cell context in which the mutation occurs. Compared with non-malignant pediatric pontine tissue, we identify and functionally validate both shared and variant-specific pathophysiology. Altogether, we provide a powerful resource of epigenomic data in 25 primary DIPG samples and 5 rare normal pediatric pontine tissue samples, revealing clinically relevant functional distinctions previously unidentified in DIPG.
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