Mammalian circadian clocks consist of complex integrated feedback loops1,2,3,4,5,6,7,8,9,10 that cannot be elucidated without comprehensive measurement of system dynamics and determination of network structures11. To dissect such a complicated system, we took a systems-biological approach based on genomic, molecular and cell biological techniques. We profiled suprachiasmatic nuclei and liver genome-wide expression patterns under light/dark cycles and constant darkness. We determined transcription start sites of human orthologues for newly identified cycling genes and then performed bioinformatical searches for relationships between time-of-day specific expression and transcription factor response elements around transcription start sites. Here we demonstrate the role of the Rev-ErbA/ROR response element in gene expression during circadian night, which is in phase with Bmal1 and in antiphase to Per2 oscillations. This role was verified using an in vitro validation system, in which cultured fibroblasts transiently transfected with clock-controlled reporter vectors exhibited robust circadian bioluminescence12.
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We thank T. Kojima, T. Katakura and H. Urata for technical assistance. This study was performed as a part of a research and development project of the Industrial Science and Technology Program supported by NEDO (New Energy and Industrial Technology Development Organization).
The authors declare that they have no competing financial interests.
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