[A systems-biological approach in drug discovery for circadian rhythm disorders]

A paradigm shift is occurring in all over the biological fields, from the molecular level to the system level. However, systematic and efficient method to dissect the complicated genetic network is still immature. To dissect such a complicated system, we took a systems-biological approach based on genomic, molecular and cell biological techniques and applied to mammalian circadian rhythms, one of the most complicated biological systems. We profiled suprachiasmatic nuclei (SCN) and liver genome-wide expression patterns under light/dark (LD) cycles and constant darkness (DD). We extensively determined transcription start sites (TSS) 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 TSS. 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 antiphase to Per2 oscillations. This role was verified using a newly developed in vitro validation system, in which cultured fibroblasts transiently transfected with clock-controlled reporter vectors exhibited robust circadian bioluminescence. The systems-biological approach used here enhances accurate and comprehensive measurement of circadian dynamics, accelerates extensive identification of clockwork circuits, and leads to systems-level understanding of mammalian circadian clocks.