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

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Version: Final published version
Serval ID
serval:BIB_E8E1A136A4E5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The genomic landscape of human cellular circadian variation points to a novel role for the signalosome.
Journal
eLife
Author(s)
Gaspar L., Howald C., Popadin K., Maier B., Mauvoisin D., Moriggi E., Gutierrez-Arcelus M., Falconnet E., Borel C., Kunz D., Kramer A., Gachon F., Dermitzakis E.T., Antonarakis S.E., Brown S.A.
ISSN
2050-084X (Electronic)
ISSN-L
2050-084X
Publication state
Published
Issued date
04/09/2017
Peer-reviewed
Oui
Volume
6
Pages
1-23
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
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.
Keywords
ARNTL Transcription Factors/metabolism, Biological Variation, Population, COP9 Signalosome Complex/metabolism, Circadian Rhythm, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Protein Stability, Proteins/metabolism, cell biology, circadian, fibroblast, genetic variation, genome-wide association, human, protein stability, signalosome
Pubmed
Web of science
Open Access
Yes
Create date
22/09/2017 10:15
Last modification date
17/09/2020 8:24
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