1. Cancer Biology
  2. Chromosomes and Gene Expression
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Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

  1. Jay F Sarthy
  2. Michael P Meers
  3. Derek H Janssens
  4. Jorja G Henikoff
  5. Heather Feldman
  6. Patrick J Paddison
  7. Christina M Lockwood
  8. Nicholas A Vitanza
  9. James M Olson
  10. Kami Ahmad  Is a corresponding author
  11. Steven Henikoff  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States
  2. University of Washington, United States
  3. Seattle Childrens Hospital, United States
Research Article
  • Cited 5
  • Views 1,994
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Cite this article as: eLife 2020;9:e61090 doi: 10.7554/eLife.61090

Abstract

Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNA replication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.

Article and author information

Author details

  1. Jay F Sarthy

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Michael P Meers

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Derek H Janssens

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jorja G Henikoff

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Heather Feldman

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Patrick J Paddison

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Christina M Lockwood

    Department of Laboratory Medicine, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Nicholas A Vitanza

    Cancer and Blood Disorders, Seattle Childrens Hospital, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. James M Olson

    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Kami Ahmad

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    kahmad@fredhutch.org
    Competing interests
    The authors declare that no competing interests exist.
  11. Steven Henikoff

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    steveh@fhcrc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7621-8685

Funding

Howard Hughes Medical Institute (Henikoff)

  • Steven Henikoff

National Institutes of Health (R01GM108699)

  • Kami Ahmad

Alex's Lemonade Stand Foundation for Childhood Cancer (Sarthy)

  • Jay F Sarthy

Damon Runyon Cancer Research Foundation (Sarthy)

  • Jay F Sarthy

National Institutes of Health (T32 CA009351)

  • Jay F Sarthy

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jerry L Workman, Stowers Institute for Medical Research, United States

Publication history

  1. Received: July 15, 2020
  2. Accepted: September 8, 2020
  3. Accepted Manuscript published: September 9, 2020 (version 1)
  4. Version of Record published: September 25, 2020 (version 2)

Copyright

© 2020, Sarthy et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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