The genomic landscape of human cellular circadian variation points to a novel role for the signalosome
- Institute of Pharmacology and Toxicology, University of Zurich, Switzerland
- University of Geneva, Switzerland
- Charité-Universitätsmedizin Berlin, Germany
- University of Lausanne, Switzerland
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Germany
- Charité Universitätsmedizin Berlin, Germany
- 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
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GencordPublicly available at the NCBI Sequence Read Archive (accession no. EGAD00000000027).
Article and author information
Author details
Konstantin Popadin
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.
Reviewing Editor
- Patrick Nolan, Medical Research Council Harwell, United Kingdom
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.
Version history
- Received: February 15, 2017
- Accepted: September 1, 2017
- Accepted Manuscript published: September 4, 2017 (version 1)
- 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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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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