Journal
ELIFE
Volume 2, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.00426
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Funding
- Howard Hughes Medical Institute [H012233]
- National Institutes of Health [R37 MH39592, U01 MH61915, P50 MH074924, F32 DA024556, R15 GM086825]
- National Science Foundation Science and Technology Center for Biological Timing [DIR-8920162]
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Genetic and molecular approaches have been critical for elucidating the mechanism of the mammalian circadian clock. Here, we demonstrate that the Clock Delta 19 mutant behavioral phenotype is significantly modified by mouse strain genetic background. We map a suppressor of the Clock Delta 19 mutation to a similar to 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 CLOCK Delta 19: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.
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