H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers

  1. Dong Fang
  2. Haiyun Gan
  3. Liang Cheng
  4. Jeong-Heon Lee
  5. Hui Zhou
  6. Jann N Sarkaria
  7. David J Daniels
  8. Zhiguo Zhang  Is a corresponding author
  1. Columbia University, United States
  2. Mayo Clinic, United States

Abstract

Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27 trimethylation, and hence silencing of tumor suppressor genes.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE94834

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Dong Fang

    Department of Pediatrics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Haiyun Gan

    Department of Pediatrics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Liang Cheng

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeong-Heon Lee

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hui Zhou

    Department of Pediatrics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jann N Sarkaria

    Department of Radiation Oncology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. David J Daniels

    Department of Neurosurgery, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Zhiguo Zhang

    Department of Pediatrics, Columbia University, New York, United States
    For correspondence
    zz2401@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9451-2685

Funding

National Institutes of Health (CA204297)

  • Zhiguo Zhang

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: March 15, 2018
  2. Accepted: June 21, 2018
  3. Accepted Manuscript published: June 22, 2018 (version 1)
  4. Version of Record published: July 5, 2018 (version 2)

Copyright

© 2018, Fang 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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  1. Dong Fang
  2. Haiyun Gan
  3. Liang Cheng
  4. Jeong-Heon Lee
  5. Hui Zhou
  6. Jann N Sarkaria
  7. David J Daniels
  8. Zhiguo Zhang
(2018)
H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers
eLife 7:e36696.
https://doi.org/10.7554/eLife.36696

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