Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State.
Journal article

Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State.

  • Nagaraja S Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Quezada MA Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
  • Gillespie SM Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
  • Arzt M Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
  • Lennon JJ Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
  • Woo PJ Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
  • Hovestadt V Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Kambhampati M Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
  • Filbin MG Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA, USA.
  • Suva ML Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Nazarian J Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA; Department of Oncology, University Children's Hospital, Zurich, Switzerland.
  • Monje M Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: mmonje@stanford.edu.
Show more…
  • 2019-10-08
Published in:
  • Molecular cell. - 2019
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/30087
Statistics

Document views: 5 File downloads: