The genomic landscape of human cellular circadian variation points to a novel role for the signalosome
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
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.
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Further reading
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Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
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