ID2 (Inhibitor of DNA Binding 2) Is a Rhythmically Expressed Transcriptional Repressor Required for Circadian Clock Output in Mouse Liver

Id2 is a helix-loop-helix transcription factor gene expressed in a circadian manner in multiple tissues with a phase-locked relationship with canonical clock genes (1). Our previous studies have identified circadian phenotypes in Id2 null mice, including enhanced photo-entrainment and disruption of activity rhythms, and have demonstrated a potent inhibitory effect of ID proteins upon CLOCK-BMAL1 transactivation of clock gene and clock-controlled gene activity (1). We have now begun to explore the potential role that ID2 may play in specifically regulating clock output. Here we show that ID2 protein is rhythmically expressed in mouse liver. Time-of-day-specific liver gene expression in Id2(+/+) and Id2(-/-) mice under circadian conditions was studied using DNA microarray analysis, identifying 651 differentially expressed genes, including a subset of 318 genes deemed rhythmically expressed in other studies. Examination of individual time courses reveals that these genes are dysregulated in a highly time-specific manner. A cohort of different functional groups were identified, including genes associated with glucose and lipid metabolism, e.g. serum protein Igfbp1 and lipoprotein lipase. We also reveal that the Id2(-/-) mice show a reduction in lipid storage in the liver and white adipose tissue, suggesting that disruption of normal circadian activity of components of lipid metabolism can result in overt physiological alterations. These data reveal a role for the transcriptional repressor ID2 as a circadian output regulator in the periphery.