A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo.
The mouse Period2 (mPer2) locus is an essential negative-feedback element of the mammalian circadian-clock mechanism. Recent work has shown that mPer2 circadian gene expression persists in both central and peripheral tissues. Here, we analyze the mouse mPer2 promoter and identify a circadian enhancer (E2) with a noncanonical 5'-CACGTT-3' E-box located 20 bp upstream of the mPer2 transcription start site. The E2 enhancer accounts for most circadian transcriptional drive of the mPer2 locus by CLOCK:BMAL1, is a major site of DNaseI hypersensitivity in this region, and is constitutively bound by a transcriptional complex containing the CLOCK protein. Importantly, the E2 enhancer is sufficient to drive self-sustained circadian rhythms of luciferase activity in central and peripheral tissues from mPer2-E2::Luciferase transgenic mice with tissue-specific phase and period characteristics. Last, genetic analysis with mutations in Clock and Bmal1 shows that the E2 enhancer is a target of CLOCK and BMAL1 in vivo.
Yoo
Seung-Hee
SH
Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA.
Ko
Caroline H
CH
Lowrey
Phillip L
PL
Buhr
Ethan D
ED
Song
Eun-joo
EJ
Chang
Suhwan
S
Yoo
Ook Joon
OJ
Yamazaki
Shin
S
Lee
Choogon
C
Takahashi
Joseph S
JS
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D002940:Circadian Rhythm / Q000235:genetics*; D024721:E-Box Elements; D004742:Enhancer Elements, Genetic; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics*; D056950:Period Circadian Proteins; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D008156:Luciferases; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C421902:PER2 protein, human; C513312:Per2 protein, mouse; C538943:CLOCK protein, human; C538944:Clock protein, mouse