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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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (39), p.14946-14951 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1073/pnas.0802636105 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0802636105</identifier><identifier>PMID: 18815372</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2008-09, Vol.105 (39), p.14946-14951</ispartof><rights>Copyright 2008 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Sep 30, 2008</rights><rights>2008 by The National Academy of Sciences of the USA</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-4e7da547508a82a9879a48da56de576ae6a975a2655c12059cc6b1d6654c6d6d3</citedby><cites>FETCH-LOGICAL-c523t-4e7da547508a82a9879a48da56de576ae6a975a2655c12059cc6b1d6654c6d6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/105/39.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25464341$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25464341$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18815372$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kumaki, Yuichi</creatorcontrib><creatorcontrib>Ukai-Tadenuma, Maki</creatorcontrib><creatorcontrib>Uno, Ken-ichiro D</creatorcontrib><creatorcontrib>Nishio, Junko</creatorcontrib><creatorcontrib>Masumoto, Koh-hei</creatorcontrib><creatorcontrib>Nagano, Mamoru</creatorcontrib><creatorcontrib>Komori, Takashi</creatorcontrib><creatorcontrib>Shigeyoshi, Yasufumi</creatorcontrib><creatorcontrib>Hogenesch, John B</creatorcontrib><creatorcontrib>Ueda, Hiroki R</creatorcontrib><title>Analysis and synthesis of high-amplitude Cis-elements in the mammalian circadian clock</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Mammalian circadian clocks consist of regulatory loops mediated by Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements. 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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. 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| 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 |
| title | Analysis and synthesis of high-amplitude Cis-elements in the mammalian circadian clock |
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