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

Abstract

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.Circadian rhythms are endogenous biochemical, physiological, and behavioral 24-h oscillations that persist under constant conditions and are generated by a series of intracellular transcriptional-translational feedback loops, composed of positive and negative components (2, 3). The positive loop consists of CLOCK (circadian locomotor output cycle kaput) and BMAL1

Alterations of Hepatic Metabolism in Chronic Kidney Disease via D-box-binding Protein Aggravate the Renal Dysfunction

“…Transcription of Dbp has been shown to be positively regulated by CLOCK-BMAL1, which binds to an E-box in its promoter (44). Conversely, CLOCK-BMAL1-dependent transcription is antagonized by inhibitor of DNA binding 2 (ID2), which prevents the complex from binding to E-boxes (45,46). In agreement with these findings, we found that among the mRNAs studied, only Id2 mRNA levels were increased in 5/6Nx serum (Fig.…”

Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression

“…These proteins include the helix-loop-helix transcription factors, such as Differentially Expressed in Chondorocytes-1 and -2 (DEC1 and DEC2) and Inhibitor of DNA Binding 2 (ID2). These proteins can inhibit CLOCK⅐BMAL1 activities possibly by interfering with formation of the CLOCK⅐BMAL1 complex (27)(28)(29). DEC1 protein was also reported to delay the phases of Per1, Dbp, and Nr1d1 in cells after serum synchronization (30).…”

Inhibitor of DNA Binding 4 (ID4) Regulation of Adipocyte Differentiation and Adipose Tissue Formation in Mice

“…ID2 regulates fat metabolism in adipose tissue and liver, and the loss of Id2 leads to decreased adipogenesis, both in vitro and in vivo (18,21). Like ID4, loss of ID2 in vivo severely compromised adipose tissue formation but does not block it completely.…”

“…Recently, in vitro studies have shown that ID2 and ID3 may regulate genes expressed during adipocyte differentiation, including adiponectin, hormone-sensitive lipase, and fatty-acid synthase (17,19,20). In addition to its role in adipocyte differentiation, ID2 also is known to contribute to the circadian regulation of lipid metabolism in vivo (21). The expression of another member of this family of proteins, ID4, increases in response to hormone-induced adipocyte differen-tiation, although its role in adipogenesis and adipose tissue formation is unknown (22).…”