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

• Published in: eLife 2013-04, Vol.2, p.e00426-e00426
• Main Authors: Shimomura, Kazuhiro, Kumar, Vivek, Koike, Nobuya, Kim, Tae-Kyung, Chong, Jason, Buhr, Ethan D, Whiteley, Andrew R, Low, Sharon S, Omura, Chiaki, Fenner, Deborah, Owens, Joseph R, Richards, Marc, Yoo, Seung-Hee, Hong, Hee-Kyung, Vitaterna, Martha H, Bass, Joseph, Pletcher, Mathew T, Wiltshire, Tim, Hogenesch, John, Lowrey, Phillip L, Takahashi, Joseph S
• Format: Article
• Language: English
• Subjects: Animals; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Behavior; Binding Sites; Binding, Competitive; BMAL1 protein; ChIP-Seq; Chromosome 1; Circadian Clocks - genetics; Circadian rhythm; Circadian Rhythm - genetics; Circadian rhythms; Clock gene; CLOCK Proteins - genetics; CLOCK Proteins - metabolism; Cloning; Deoxyribonucleic acid; DNA; DNA - metabolism; E-Box Elements; Gene Expression Regulation; Genes; genetic modifier; Genomes; Genomics; Genomics and Evolutionary Biology; Genotype; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; mouse genetic; Mutagenesis; Mutation; Neurobiology; Neuroscience; Neurosciences; Phenotype; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Protein Interaction Domains and Motifs; RNA, Messenger - metabolism; Signal Transduction; Single-nucleotide polymorphism; Species Specificity; Stem cells; Time Factors; Transcription, Genetic; Transcriptional Activation; Upstream Stimulatory Factors - genetics; Upstream Stimulatory Factors - metabolism; USF1
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.00426

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. DOI:http://dx.doi.org/10.7554/eLife.00426.001.