Genome-Wide and Phase-Specific DNA-Binding Rhythms of BMAL1 Control Circadian Output Functions in Mouse Liver
(A) BMAL1 targets are highly enriched for robustly cycling mRNAs. Distribution of –log10 (p-value) are shown for all genes (black), liver-specific genes (see Materials and Methods) (grey), and BMAL1 targets (red). The vertical dashed line represents p = 0.05. Expression data are from mouse liver light-dark time course data . BMAL1 sites were annotated with the closest protein-coding transcript in Ensembl within a window of 10 kb. (B) Strong BMAL1 binding is associated with circadian mRNA accumulation. The sites are ranked according to their strength, and the fraction of robustly circadian mRNA patterns (Fisher test, p<0.05; see Materials and Methods) among the top x sites is shown. This fraction decreases from 100% among the top 10 sites to 29% for all sites, and this proportion is practically unchanged (31%) if we restrict our analysis to only rhythmic BMAL1 sites. (C) The distribution of the phase of cytosolic mRNA expression of targets of BMAL1 peaks at ZT10-ZT12. (D) BMAL1 targets with an E1-E2 element show narrower mRNA phase distribution than targets with no or single E-boxes (Rao homogeneity test for circular data , p[equality of dispersions]<0.01). E1-E2-6 and E1-E2-7 represent, respectively, the subgroup of E1-E2 sites with a spacer of 6 bp and 7 bp.