System-level identification of transcriptional circuits underlying mammalian circadian clocks (original) (raw)

Nature Genetics volume 37, pages 187–192 (2005)Cite this article

Abstract

Mammalian circadian clocks consist of complexly integrated regulatory loops1,2,3,4,5, making it difficult to elucidate them without both the accurate measurement of system dynamics and the comprehensive identification of network circuits6. Toward a system-level understanding of this transcriptional circuitry, we identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of their transcriptional dynamics. Here we report the roles of E/E′ boxes, DBP/E4BP4 binding elements7 and RevErbA/ROR binding elements8 in nine, seven and six genes, respectively. Our results indicate that circadian transcriptional circuits are governed by two design principles: regulation of E/E′ boxes and RevErbA/ROR binding elements follows a repressor-precedes-activator pattern, resulting in delayed transcriptional activity, whereas regulation of DBP/E4BP4 binding elements follows a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Our analysis further suggests that regulation of E/E′ boxes is a topological vulnerability in mammalian circadian clocks, a concept that has been functionally verified using in vitro phenotype assay systems.

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Acknowledgements

We thank H. Tei and Y. Sakaki for Arntl, Clock and Cry1 expression vectors; T. Kojima, T. Katakura and H. Urata for technical assistance; and D. Sipp and Y. Minami for critical reading of the manuscript. This research was done as part of a research and development project of the Industrial Science and Technology Program supported by the New Energy and Industrial Technology Development Organization and, in part, by intramural Grant-in-Aid from the CDB, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grant-in-Aid for Strategic Programs in R & D from the Institute of Physical and Chemical Research and Grant-in-Aid for Scientific Research from the New Energy and Industrial Technology Development Organization.

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Authors and Affiliations

  1. Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan
    Hiroki R Ueda, Satoko Hayashi, Wenbin Chen & Seiichi Hashimoto
  2. Laboratory for Systems Biology, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Hyogo, Japan
    Hiroki R Ueda
  3. Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo, 113-0033, Japan
    Hiroki R Ueda & Masamitsu Iino
  4. Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1, Higashi, Tsukuba, Ibaraki, 305-8566, Japan
    Motoaki Sano & Masayuki Machida
  5. Department of Anatomy and Neurobiology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osakasayama City, 589-8511, Osaka, Japan
    Yasufumi Shigeyoshi

Authors

  1. Hiroki R Ueda
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  2. Satoko Hayashi
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  3. Wenbin Chen
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  4. Motoaki Sano
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  5. Masayuki Machida
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  6. Yasufumi Shigeyoshi
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  7. Masamitsu Iino
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  8. Seiichi Hashimoto
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Correspondence toHiroki R Ueda.

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Ueda, H., Hayashi, S., Chen, W. et al. System-level identification of transcriptional circuits underlying mammalian circadian clocks.Nat Genet 37, 187–192 (2005). https://doi.org/10.1038/ng1504

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