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.

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.

Metrics

  • 1,421
    views
  • 322
    downloads
  • 12
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. 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

Share this article

https://doi.org/10.7554/eLife.24994

Further reading

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

    1. Cell Biology
    Affiong Ika Oqua, Kin Chao ... Alejandra Tomas
    Research Article

    G protein-coupled receptors (GPCRs) are integral membrane proteins which closely interact with their plasma membrane lipid microenvironment. Cholesterol is a lipid enriched at the plasma membrane with pivotal roles in the control of membrane fluidity and maintenance of membrane microarchitecture, directly impacting on GPCR stability, dynamics, and function. Cholesterol extraction from pancreatic beta cells has previously been shown to disrupt the internalisation, clustering, and cAMP responses of the glucagon-like peptide-1 receptor (GLP-1R), a class B1 GPCR with key roles in the control of blood glucose levels via the potentiation of insulin secretion in beta cells and weight reduction via the modulation of brain appetite control centres. Here, we unveil the detrimental effect of a high cholesterol diet on GLP-1R-dependent glucoregulation in vivo, and the improvement in GLP-1R function that a reduction in cholesterol synthesis using simvastatin exerts in pancreatic islets. We next identify and map sites of cholesterol high occupancy and residence time on active vs inactive GLP-1Rs using coarse-grained molecular dynamics (cgMD) simulations, followed by a screen of key residues selected from these sites and detailed analyses of the effects of mutating one of these, Val229, to alanine on GLP-1R-cholesterol interactions, plasma membrane behaviours, clustering, trafficking and signalling in INS-1 832/3 rat pancreatic beta cells and primary mouse islets, unveiling an improved insulin secretion profile for the V229A mutant receptor. This study (1) highlights the role of cholesterol in regulating GLP-1R responses in vivo; (2) provides a detailed map of GLP-1R - cholesterol binding sites in model membranes; (3) validates their functional relevance in beta cells; and (4) highlights their potential as locations for the rational design of novel allosteric modulators with the capacity to fine-tune GLP-1R responses.