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

Version 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.

Metrics

  • 5,360
    Page views
  • 620
    Downloads
  • 28
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.54993

Further reading

    1. Cancer Biology
    2. Cell Biology
    Julian J A Hoving, Elizabeth Harford-Wright ... Alison C Lloyd
    Research Article

    Collective cell migration is fundamental for the development of organisms and in the adult, for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact inhibition of locomotion (CIL), a local repulsive force, can propel the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during rat Schwann cell (SC) collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin is required to present the repulsive Slit2/Slit3 signal at the cell-surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective Schwann cell migration, resulting in adherent, nonmigratory cell clusters. Moreover, analysis of ex vivo explants from mice following sciatic nerve injury showed that inhibition of Slit2 decreased Schwann cell collective migration and increased clustering of Schwann cells within the nerve bridge. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.

    1. Cancer Biology
    2. Structural Biology and Molecular Biophysics
    Johannes Paladini, Annalena Maier ... Stephan Grzesiek
    Research Article

    Abelson tyrosine kinase (Abl) is regulated by the arrangement of its regulatory core, consisting sequentially of the SH3, SH2, and kinase (KD) domains, where an assembled or disassembled core corresponds to low or high kinase activity, respectively. It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. Here, we demonstrate that the C-terminal αI-helix exerts an additional force toward the SH2 domain, which correlates both with kinase activity and type II inhibitor-induced disassembly. The αI-helix mutation E528K, which is responsible for the ABL1 malformation syndrome, strongly activates Abl by breaking a salt bridge with the KD C-lobe and thereby increasing the force onto the SH2 domain. In contrast, the allosteric inhibitor asciminib strongly reduces Abl’s activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.