Analysis and synthesis of high-amplitude Cis-elements in the mammalian circadian clock

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...

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Published in	Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 39; pp. 14946 - 14951
Main Authors	Kumaki, Yuichi, Ukai-Tadenuma, Maki, Uno, Ken-ichiro D, Nishio, Junko, Masumoto, Koh-hei, Nagano, Mamoru, Komori, Takashi, Shigeyoshi, Yasufumi, Hogenesch, John B, Ueda, Hiroki R
Format	Journal Article
Language	English
Published	United States National Academy of Sciences 30.09.2008 National Acad Sciences
Subjects	Animals ARNTL Transcription Factors Base Sequence Basic Helix-Loop-Helix Transcription Factors - metabolism Basic-Leucine Zipper Transcription Factors Binding sites Binding, Competitive Biochemistry Biological Sciences Bioluminescence Circadian Rhythm - genetics CLOCK Proteins Comparative genomics Databases, Genetic DNA-Binding Proteins - metabolism Enhancer Elements, Genetic Evolution Gene expression Gene Expression Regulation Genes Genomes Genomics Humans Mammals Mice Promoter Regions, Genetic Response elements Sequence Analysis, DNA Trans-Activators - metabolism Transcription factors Transcription Factors - metabolism
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Abstract	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.
AbstractList	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. 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. Mammalian circadian clocks consist of regulatory loops mediated by Clock/Bmall-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/Bmal 1-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. [PUBLICATION ABSTRACT] 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. comparative genomics promoter and enhancer database synthetic biology systems biology transcription
Author	Kumaki, Yuichi Hogenesch, John B Uno, Ken-ichiro D Nagano, Mamoru Masumoto, Koh-hei Komori, Takashi Ukai-Tadenuma, Maki Ueda, Hiroki R Nishio, Junko Shigeyoshi, Yasufumi
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Laboratory for Mammalian Epigenetic Studies, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. Edited by Joseph S. Takahashi, Northwestern University, Evanston, IL, and approved August 15, 2008 Author contributions: J.B.H. and H.R.U. designed research; Y.K., M.U., K.D.U., J.N., K.M., M.N., and Y.S. performed research; Y.K. and T.K. contributed new analytic tools; Y.K. analyzed data; and Y.K., J.B.H., and H.R.U. wrote the paper.
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Snippet	Mammalian circadian clocks consist of regulatory loops mediated by Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements.... Mammalian circadian clocks consist of regulatory loops mediated by Clock/Bmall-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements....
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SubjectTerms	Animals ARNTL Transcription Factors Base Sequence Basic Helix-Loop-Helix Transcription Factors - metabolism Basic-Leucine Zipper Transcription Factors Binding sites Binding, Competitive Biochemistry Biological Sciences Bioluminescence Circadian Rhythm - genetics CLOCK Proteins Comparative genomics Databases, Genetic DNA-Binding Proteins - metabolism Enhancer Elements, Genetic Evolution Gene expression Gene Expression Regulation Genes Genomes Genomics Humans Mammals Mice Promoter Regions, Genetic Response elements Sequence Analysis, DNA Trans-Activators - metabolism Transcription factors Transcription Factors - metabolism
Title	Analysis and synthesis of high-amplitude Cis-elements in the mammalian circadian clock
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