title: Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice.
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. DOI:http://dx.doi.org/10.7554/eLife.00426.001.
authors.affiliation: Center for Functional Genomics, Department of Neurobiology, Center for Sleep and Circadian Biology , Northwestern University , Evanston , United States.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shimomura
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.forename: Nobuya
authors.initials: N
authors.lastname: Koike
authors.forename: Tae-Kyung
authors.initials: TK
authors.lastname: Kim
authors.forename: Jason
authors.initials: J
authors.lastname: Chong
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Buhr
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Whiteley
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Low
authors.forename: Chiaki
authors.initials: C
authors.lastname: Omura
authors.forename: Deborah
authors.initials: D
authors.lastname: Fenner
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Owens
authors.forename: Marc
authors.initials: M
authors.lastname: Richards
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yoo
authors.forename: Hee-Kyung
authors.initials: HK
authors.lastname: Hong
authors.forename: Martha H
authors.initials: MH
authors.lastname: Vitaterna
authors.forename: Joseph
authors.initials: J
authors.lastname: Bass
authors.forename: Mathew T
authors.initials: MT
authors.lastname: Pletcher
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.forename: John
authors.initials: J
authors.lastname: Hogenesch
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Lowrey
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D057906:Circadian Clocks / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D024721:E-Box Elements; D005786:Gene Expression Regulation; D005838:Genotype; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D012333:RNA, Messenger; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; D004247:DNA; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: ChIP-Seq; Clock gene; Mouse; USF1; circadian rhythms; genetic modifier; mouse genetics