The genomic landscape of human cellular circadian variation points to a novel role for the signalosome

  1. Ludmila Gaspar
  2. Cedric Howald
  3. Konstantin Popadin
  4. Bert Maier
  5. Daniel Mauvoisin
  6. Ermanno Moriggi
  7. Maria Gutierrez-Arcelus
  8. Emilie Falconnet
  9. Christelle Borel
  10. Dieter Kunz
  11. Achim Kramer
  12. Frederic Gachon
  13. Emmanouil T Dermitzakis
  14. Stylianos E Antonarakis
  15. Steven A Brown  Is a corresponding author
  1. Institute of Pharmacology and Toxicology, University of Zurich, Switzerland
  2. University of Geneva, Switzerland
  3. Charité-Universitätsmedizin Berlin, Germany
  4. University of Lausanne, Switzerland
  5. Institute of Physiology, Charité-Universitätsmedizin Berlin, Germany
  6. Charité Universitätsmedizin Berlin, Germany
  7. Institute of Pharmacology and Toxicology, University of Zürich, Switzerland

Abstract

The importance of natural gene expression variation for human behavior is undisputed, but its impact on circadian physiology remains mostly unexplored. Using umbilical cord fibroblasts, we have determined by genome-wide association how common genetic variation impacts upon cellular circadian function. Gene set enrichment points to differences in protein catabolism as one major source of clock variation in humans. The two most significant alleles regulated expression of COPS7B, a subunit of the COP9 signalosome. We further show that the signalosome complex is imported into the nucleus in timed fashion to stabilize the essential circadian protein BMAL1, a novel mechanism to oppose its proteasome-mediated degradation. Thus, circadian clock properties depend in part upon a genetically-encoded competition between stabilizing and destabilizing forces, and genetic alterations in these mechanisms provide one explanation for human chronotype.

Data availability

The following previously published data sets were used
    1. Dermitzakis
    2. E
    (2011) Gencord
    Publicly available at the NCBI Sequence Read Archive (accession no. EGAD00000000027).

Article and author information

Author details

  1. Ludmila Gaspar

    Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Cedric Howald

    Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Konstantin Popadin

    Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2117-6086
  4. Bert Maier

    Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Daniel Mauvoisin

    Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0571-0741
  6. Ermanno Moriggi

    Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4600-5777
  7. Maria Gutierrez-Arcelus

    Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  8. Emilie Falconnet

    Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  9. Christelle Borel

    Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  10. Dieter Kunz

    Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Achim Kramer

    Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Frederic Gachon

    Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9279-9707
  13. Emmanouil T Dermitzakis

    Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  14. Stylianos E Antonarakis

    Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  15. Steven A Brown

    Institute of Pharmacology and Toxicology, University of Zürich, Zurich, Switzerland
    For correspondence
    Steven.brown@pharma.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5511-568X

Funding

Swiss National Science Foundation (CRSII3_160741)

  • Steven A Brown

Zurich Hospital (CRPPSleep&Health)

  • Steven A Brown

Velux Foundation (923)

  • Steven A Brown

European Research Council (ERC-2010-StG-260988)

  • Frederic Gachon

Leenards Foundation (Grant)

  • Frederic Gachon

Immanuel Kant Baltic University (5 Top 100 Russian Academic Excellence Project)

  • Konstantin Popadin

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 animal experiments were conducted with the approval of relevant cantonal veterinary authorities in Switzerland, after prior review of all procedures and planned experiments.

Human subjects: All human samples used in these studies were obtained after approval of all protocols and procedures by the relevant responsible authorities (of the University Hospital Geneva, CH; and Charite Universitätsmedezin, Berlin, DE), and prior written informed consent was obtained from all subjects or their legal guardians.

Reviewing Editor

  1. Patrick Nolan, Medical Research Council Harwell, United Kingdom

Publication history

  1. Received: January 10, 2017
  2. Accepted: September 1, 2017
  3. Accepted Manuscript published: September 4, 2017 (version 1)
  4. Version of Record published: September 15, 2017 (version 2)

Copyright

© 2017, Gaspar 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. Ludmila Gaspar
  2. Cedric Howald
  3. Konstantin Popadin
  4. Bert Maier
  5. Daniel Mauvoisin
  6. Ermanno Moriggi
  7. Maria Gutierrez-Arcelus
  8. Emilie Falconnet
  9. Christelle Borel
  10. Dieter Kunz
  11. Achim Kramer
  12. Frederic Gachon
  13. Emmanouil T Dermitzakis
  14. Stylianos E Antonarakis
  15. Steven A Brown
(2017)
The genomic landscape of human cellular circadian variation points to a novel role for the signalosome
eLife 6:e24994.
https://doi.org/10.7554/eLife.24994

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