1. Cell Biology
  2. Genetics and Genomics

A trans-eQTL network regulates osteoclast multinucleation and bone mass

  1. Marie Pereira  Is a corresponding author
  2. Jeong-Hun Ko
  3. John Logan
  4. Hayley Protheroe
  5. Kee-Beom Kim
  6. Amelia Li Min Tan
  7. Kwon-Sik Park
  8. Maxime Rotival
  9. Enrico Petretto
  10. J H Duncan Bassett  Is a corresponding author
  11. Graham R Williams  Is a corresponding author
  12. Jacques Behmoaras  Is a corresponding author
  1. Imperial College London, United Kingdom
  2. University of Virginia School of Medicine, United States
  3. Duke-NUS Medical School, Singapore
  4. Institut Pasteur, Centre National de la Recherche Scientifique, UMR 2000, France
https://doi.org/10.7554/eLife.55549
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  1. Marie Pereira
  2. Jeong-Hun Ko
  3. John Logan
  4. Hayley Protheroe
  5. Kee-Beom Kim
  6. Amelia Li Min Tan
  7. Kwon-Sik Park
  8. Maxime Rotival
  9. Enrico Petretto
  10. J H Duncan Bassett
  11. Graham R Williams
  12. Jacques Behmoaras
(2020)
A trans-eQTL network regulates osteoclast multinucleation and bone mass
eLife 9:e55549.
https://doi.org/10.7554/eLife.55549
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Abstract

Functional characterisation of cell-type specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb-/-, Atp8b2+/-, Igsf8-/-, Eml1-/-, Appl2-/-, Deptor-/-) and myeloid-specific Slc40a1 knockout mice displayed abnormal bone phenotypes. We report opposing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast multinucleation and bone mass.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Marie Pereira

    Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    For correspondence
    m.pereira@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0711-3385

  2. Jeong-Hun Ko

    Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. John Logan

    Molecular Endocrinology Laboratory, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Hayley Protheroe

    Molecular Endocrinology Laboratory, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Kee-Beom Kim

    Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Amelia Li Min Tan

    Medical school, Duke-NUS Medical School, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.

  7. Kwon-Sik Park

    Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Maxime Rotival

    Human Evolutionary Genetics Unit, Institut Pasteur, Centre National de la Recherche Scientifique, UMR 2000, Paris, France
    Competing interests
    The authors declare that no competing interests exist.

  9. Enrico Petretto

    Medical school, Duke-NUS Medical School, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.

  10. J H Duncan Bassett

    Molecular Endocrinology Laboratory, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
    For correspondence
    d.bassett@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

  11. Graham R Williams

    Molecular Endocrinology Laboratory, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
    For correspondence
    graham.williams@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8555-8219

  12. Jacques Behmoaras

    Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    For correspondence
    jacques.behmoaras@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Funding

Medical Research Council (MR/N01121X/1)

  • J H Duncan Bassett
  • Graham R Williams
  • Jacques Behmoaras

Wellcome (101123)

  • J H Duncan Bassett
  • Graham R Williams

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

Ethics

Animal experimentation: All studies were performed in accordance to the U.K. Animal (Scientific Procedures) Act 1986, the ARRIVE guidelines, the EU Directive 2010/63/EU for animal experiments and practices prescribed by the National Institutes of Health in the United States.

Reviewing Editor

  1. Charles Farber, University of Virginia, United States

Version history

  1. Received: January 28, 2020
  2. Accepted: June 12, 2020
  3. Accepted Manuscript published: June 19, 2020 (version 1)
  4. Version of Record published: July 10, 2020 (version 2)

Copyright

© 2020, Pereira 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. Marie Pereira
  2. Jeong-Hun Ko
  3. John Logan
  4. Hayley Protheroe
  5. Kee-Beom Kim
  6. Amelia Li Min Tan
  7. Kwon-Sik Park
  8. Maxime Rotival
  9. Enrico Petretto
  10. J H Duncan Bassett
  11. Graham R Williams
  12. Jacques Behmoaras
(2020)
A trans-eQTL network regulates osteoclast multinucleation and bone mass
eLife 9:e55549.
https://doi.org/10.7554/eLife.55549

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