Nature Genetics
37, 187 - 192 (2005)
Published online: 23 January 2005; | doi:10.1038/ng1504
System-level identification of transcriptional circuits underlying mammalian circadian clocksHiroki R Ueda1, 2, 3, Satoko Hayashi1, Wenbin Chen1, Motoaki Sano4, Masayuki Machida4, Yasufumi Shigeyoshi5, Masamitsu Iino3
& Seiichi Hashimoto11
Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. 2
Laboratory for Systems Biology, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. 3
Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-0033, Japan. 4
Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1, Higashi, Tsukuba, Ibaraki, 305-8566, Japan. 5
Department of Anatomy and Neurobiology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osakasayama City, Osaka 589-8511, Japan.
Correspondence should be addressed to Hiroki R Ueda uedah-tky@umin.ac.jpMammalian 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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