Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 39, Pages 14946-14951Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802636105
Keywords
comparative genomics; promoter and enhancer database; synthetic biology; systems biology; transcription
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Funding
- RIKEN Research Collaborations with Industry Program
- RIKEN Center for Developmental Biology
- New Energy and Industrial Technology Development Organization (NEDO)
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- National Institute of Mental Health and National Institute of Neurological Disorders and Stroke of the National Institutes of Health [P50MH074924-01, 1R01NS054794-01A2]
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Mammalian circadian clocks consist of regulatory loops mediated by Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements. As a step toward system-level understanding of the dynamic transcriptional regulation of the oscillator, we constructed and used a mammalian promoter/enhancer database (http://promoter.cdb.riken.jp/) with computational models of the Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements to predict new targets of the clock and subsequently validated these targets at the level of the cell and organism. We further demonstrated the predictive nature of these models by generating and testing synthetic regulatory elements that do not occur in nature and showed that these elements produced high-amplitude circadian gene regulation. Biochemical experiments to characterize these synthetic elements revealed the importance of the affinity balance between transactivators and transrepressors in generating high-amplitude circadian transcriptional output. These results highlight the power of comparative genomics approaches for system-level identification and knowledge-based design of dynamic regulatory circuits.
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