NuRD subunit CHD4 regulates super-enhancer accessibility in Rhabdomyosarcoma and represents a general tumor dependency

  1. Joana G Marques
  2. Berkley E Gryder
  3. Blaz Pavlovic
  4. Yeonjoo Chung
  5. Quy A Ngo
  6. Fabian Frommelt
  7. Matthias Gstaiger
  8. Young Song
  9. Katharina Benischke
  10. Dominik Laubscher
  11. Marco Wachtel
  12. Javed Khan
  13. Beat W Schäfer  Is a corresponding author
  1. University Children's Hospital, Switzerland
  2. Center for Cancer Research, National Institutes of Health, United States
  3. ETH Zurich, Switzerland
  4. Institute of Molecular Systems Biology, Switzerland

Abstract

The NuRD complex subunit CHD4 is essential for fusion-positive rhabdomyosarcoma (FP-RMS) survival, but the mechanisms underlying this dependency are not understood. Here, a NuRD-specific CRISPR screen demonstrates that FP-RMS is particularly sensitive to CHD4 amongst the NuRD members. Mechanistically, NuRD complex containing CHD4 localizes to super-enhancers where CHD4 generates a chromatin architecture permissive for the binding of the tumor driver and fusion protein PAX3-FOXO1, allowing downstream transcription of its oncogenic program. Moreover, CHD4 depletion removes HDAC2 from the chromatin, leading to an increase and spread of histone acetylation, and prevents the positioning of RNA Polymerase 2 at promoters impeding transcription initiation. Strikingly, analysis of genome-wide cancer dependency databases identifies CHD4 as a general cancer vulnerability. Our findings describe CHD4, a classically defined repressor, as positive regulator of transcription and super-enhancer accessibility as well as establish this remodeler as an unexpected broad tumor susceptibility and promising drug target for cancer therapy.

Data availability

The proteomics dataset supporting the conclusions of this article is available in the ProteomeXchange Consortium via the PRIDE (Perez-Riverol et al., 2019) repository with the dataset identifier PXD015231 (reviewer account: username - reviewer88401@ebi.ac.uk, password - mErsCglm). High-throughput ChIP-seq and DNase data are available through Gene Expression Omnibus (GEO) Superseries with the accession number GSE140115. ChIP-seq data for H3K27ac, H3K27me3, H3K36me3, H3K4me1, H3K4me2, 587 H3K4me3, BRD4, CTCF, RAD21, HDAC2, and RNA Polymerase 2 as well as DNase I hypersensitivity data obtained for wildtype RH4 cells were previously published (Gryder et al., 2019b, 2017) and are available on the same data repository with the gene accession numbers GSE83728 and GSE116344. The RNA-seq data is available in the European Nucleotide Archive (ENA) with the accession number PRJEB34220 (reviewer account: username - Webin-53797, password - kispiCHD42019).

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

Article and author information

Author details

  1. Joana G Marques

    Oncology, University Children's Hospital, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Berkley E Gryder

    Oncogenomics Section, Center for Cancer Research, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Gaithersburg, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Blaz Pavlovic

    Oncology, University Children's Hospital, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Yeonjoo Chung

    Oncology, University Children's Hospital, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Quy A Ngo

    Oncology, University Children's Hospital, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Fabian Frommelt

    Institute of Molecular Systems Biology, ETH Zurich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3666-8005
  7. Matthias Gstaiger

    Department of Biology, Institute of Molecular Systems Biology, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  8. Young Song

    Genetics Branch, Center for Cancer Research, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Katharina Benischke

    Oncology, University Children's Hospital, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  10. Dominik Laubscher

    Oncology, University Children's Hospital, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  11. Marco Wachtel

    Oncology, University Children's Hospital, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  12. Javed Khan

    Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Beat W Schäfer

    Oncology, University Children's Hospital, Zurich, Switzerland
    For correspondence
    beat.schaefer@kispi.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5988-2915

Funding

Swiss National Science Foundation (310030_156923 and 31003A_175558)

  • Beat W Schäfer

Cancer League Switzerland (KLS-3868-02-2016)

  • Beat W Schäfer

Childhood Cancer Research Foundation Switzerland

  • Beat W Schäfer

Innovative Medicines Initiative ULTRA-DD (115766)

  • Fabian Frommelt
  • Matthias Gstaiger

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

Reviewing Editor

  1. Xiaobing Shi, Van Andel Institute, United States

Publication history

  1. Received: January 8, 2020
  2. Accepted: August 2, 2020
  3. Accepted Manuscript published: August 3, 2020 (version 1)
  4. Version of Record published: August 19, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Joana G Marques
  2. Berkley E Gryder
  3. Blaz Pavlovic
  4. Yeonjoo Chung
  5. Quy A Ngo
  6. Fabian Frommelt
  7. Matthias Gstaiger
  8. Young Song
  9. Katharina Benischke
  10. Dominik Laubscher
  11. Marco Wachtel
  12. Javed Khan
  13. Beat W Schäfer
(2020)
NuRD subunit CHD4 regulates super-enhancer accessibility in Rhabdomyosarcoma and represents a general tumor dependency
eLife 9:e54993.
https://doi.org/10.7554/eLife.54993

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