Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice

Kazuhiro Shimomura, Vivek Kumar, Nobuya Koike, Tae Kyung Kim, Jason Chong, Ethan D. Buhr, Andrew R. Whiteley, Sharon S. Low, Chiaki Omura, Deborah Fenner, Joseph R. Owens, Marc Richards, Seung Hee Yoo, Hee Kyung Hong, Martha H. Vitaterna, Joseph Bass, Mathew T. Pletcher, Tim Wiltshire, John Hogenesch, Phillip L. LowreyJoseph S. Takahashi

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Genetic and molecular approaches have been critical for elucidating the mechanism of the mammalian circadian clock. Here, we demonstrate that the ClockΔ19 mutant behavioral phenotype is significantly modified by mouse strain genetic background. We map a suppressor of the ClockΔ19 mutation to a ~900 kb interval on mouse chromosome 1 and identify the transcription factor, Usf1, as the responsible gene. A SNP in the promoter of Usf1 causes elevation of its transcript and protein in strains that suppress the Clock mutant phenotype. USF1 competes with the CLOCK:BMAL1 complex for binding to E-box sites in target genes. Saturation binding experiments demonstrate reduced affinity of the CLOCKΔ19:BMAL1 complex for E-box sites, thereby permitting increased USF1 occupancy on a genome-wide basis. We propose that USF1 is an important modulator of molecular and behavioral circadian rhythms in mammals.

Original languageEnglish (US)
Article numbere00426
JournaleLife
Volume2013
Issue number2
DOIs
StatePublished - Apr 9 2013

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Shimomura, K., Kumar, V., Koike, N., Kim, T. K., Chong, J., Buhr, E. D., Whiteley, A. R., Low, S. S., Omura, C., Fenner, D., Owens, J. R., Richards, M., Yoo, S. H., Hong, H. K., Vitaterna, M. H., Bass, J., Pletcher, M. T., Wiltshire, T., Hogenesch, J., ... Takahashi, J. S. (2013). Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice. eLife, 2013(2), [e00426]. https://doi.org/10.7554/eLife.00426