Genome-Wide and Phase-Specific DNA-Binding Rhythms of BMAL1 Control Circadian Output Functions in Mouse Liver
BMAL1 rhythmically binds thousands of sites in liver, with peak binding around ZT6. Among the targets, core oscillator genes stand out as the strongest and often exhibit multiple BMAL1 binding sites. E1-E2 elements favor strong binding and precise phase-specific gene expression. The many weaker sites are distributed among clock output programs in liver, notably carbohydrate and lipid metabolism. A hypothesis for the differential binding and circadian amplitude of mRNA outputs between core oscillator genes and clock outputs is that strong sites use cooperative interactions with other regulators, or between multiple BMAL1 sites.