A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo

Seung Hee Yoo, Caroline H. Ko, Phillip L. Lowrey, Ethan D. Buhr, Eun Joo Song, Suhwan Chang, Ook Joon Yoo, Shin Yamazaki, Choogon Lee, Joseph S. Takahashi

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

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 DNasel 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.

Original languageEnglish (US)
Pages (from-to)2608-2613
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number7
DOIs
StatePublished - Feb 15 2005

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Luciferases
CLOCK Proteins
Circadian Clocks
Transcription Initiation Site
Circadian Rhythm
Transgenic Mice
Hypersensitivity
Gene Expression
Mutation

Keywords

  • Bmal1 gene
  • Circadian clock
  • Clock gene
  • Luciferase
  • Period2 locus

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo. / Yoo, Seung Hee; Ko, Caroline H.; Lowrey, Phillip L.; Buhr, Ethan D.; Song, Eun Joo; Chang, Suhwan; Yoo, Ook Joon; Yamazaki, Shin; Lee, Choogon; Takahashi, Joseph S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 7, 15.02.2005, p. 2608-2613.

Research output: Contribution to journalArticle

Yoo, Seung Hee ; Ko, Caroline H. ; Lowrey, Phillip L. ; Buhr, Ethan D. ; Song, Eun Joo ; Chang, Suhwan ; Yoo, Ook Joon ; Yamazaki, Shin ; Lee, Choogon ; Takahashi, Joseph S. / A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 7. pp. 2608-2613.
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AU - Chang, Suhwan

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AU - Yamazaki, Shin

AU - Lee, Choogon

AU - Takahashi, Joseph S.

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N2 - 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 DNasel 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.

AB - 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 DNasel 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.

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