System-level identification
of transcriptional circuits underlying mammalian circadian clocks
Ueda H R, Hayashi S, Chen W, Sano M, Machida M, Shigeyoshi Y, Iino M and
Hashimoto S
Nat Genet (2005)
SUMMARY
Mammalian circadian clocks consist of complexly integrated regulatory loops,
making it difficult to elucidate them without both the accurate measurement
of system dynamics and the comprehensive identification of network circuits.
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 elements and RevErbA/ROR binding
elements 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.
LINK
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