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

Elife. 2017 Sep 4;6:e24994. doi: 10.7554/eLife.24994.

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: cell biology; circadian; fibroblast; genetic variation; genome-wide association; human; protein stability; signalosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • ARNTL Transcription Factors
  • ARNTL protein, human
  • COPS8 protein, human
  • Proteins
  • COP9 Signalosome Complex