The Transcriptional Repressor STRA13 Regulates a Subset of Peripheral Circadian Outputs

Abstract

Central and peripheral mammalian circadian clocks regulate a variety of behavioral and physiological processes through the rhythmic transcription of hundreds of clock-controlled genes. The circadian expression of many transcriptional regulators suggests that a major part of this circadian gene network is indirectly regulated by clock genes. Here we show that the basic helixloop-helix transcriptional repressor Stra13 is rhythmically expressed in mouse peripheral organs. The circadian transcription of Stra13 is mediated by a response element recognized by the CLOCK-BMAL1 heterodimer and located in the proximal promoter region. CLOCK-BMAL1-dependent activation of Stra13 is strongly repressed by CRY1 and also by STRA13 itself. To determine putative Stra13 output genes, we performed microarray analyses of differential gene expression in the liver between wild type and Stra13 ؊/؊ mice and identified 42 target genes including a subset of 20 previously known as clock-controlled genes. Importantly, we demonstrate that circadian gene expression of the serum protein insulin-like growth factor-binding protein 1 and of the NKG2D receptor ligand retinoic acid early transcript was suppressed in Stra13 ؊/؊ mice. These biochemical and genetic data establish a role for the basic helix-loop-helix repressor STRA13 as a circadian output regulator in the periphery.Circadian rhythms in physiology and behavior are observed in most organisms. They are generated by a self-sustained endogenous circadian clock that is reset by external time cues such as light and temperature (1). This mechanism is believed to provide organisms with an anticipatory adaptive mechanism to the daily predictable changes in their environment. Biochemical and genetic studies in various model systems have identified a molecular oscillator generated by transcriptional/ translational feedback loops. In mammals, the main loop involves the E box-mediated transcriptional activation of the Per1, Per2, Per3, Cry1, and Cry2 clock genes by the CLOCK-BMAL1 heterodimer. Then PER and CRY proteins form complexes that enter into the nucleus in a phosphorylation-dependent manner to repress the CLOCK-BMAL1-dependent transcription of their own genes, thereby generating a ϳ24-h period molecular oscillator (2). This loop controls also the rhythmic expression of the repressor REV-ERB␣, which is required for rhythmic Bmal1 transcription, comprising a second loop thought to be important for the overall robustness of the oscillator (3). In mammals, the master oscillator is present in the suprachiasmatic nuclei (SCN) 1 of the hypothalamus, which orchestrates autonomous oscillators in peripheral organs. Surprisingly, this oscillator can be observed in synchronized cultured cells ex vivo. The SCN oscillator is directly reset by light perceived and transmitted via the retinohypothalamic tract and is believed to entrain peripheral oscillators via ill-defined neurohormonal pathways. Peripheral oscillators also appear to be reset by hormonal signals and the feeding schedule (4, 5). The mechani...

Characterization of Peripheral Circadian Clocks in Adipose Tissues

“…Stra13 (Dec1) encodes a circadian-controlled transcriptional repressor/regulator of multiple genes, including several downstream circadian genes (35). Stra13 transcription is activated by CLOCK:BMAL1, whereas the STRA13 protein acts as a repressor of CLOCK:BMAL1 activity (35,36).…”

“…Stra13 transcription is activated by CLOCK:BMAL1, whereas the STRA13 protein acts as a repressor of CLOCK:BMAL1 activity (35,36). Maximal levels of Stra13 mRNA in liver have been reported to coincide with the peak of CLOCK: BMAL1 transcriptional activity (25).…”

SWItch/sucrose nonfermentable (SWI/SNF) complex subunit BAF60a integrates hepatic circadian clock and energy metabolism

“…Recent work investigating the respective contributions of feeding and of the circadian clock to hepatic rhythmic gene expression using clock-deficient mice and the temporally restricted feeding paradigm has shown that oscillations of food-induced transcripts, including those from the gluconeogenic and fatty acid oxidation pathways, are modulated and consolidated by the clock. 37 Reciprocally, the robustness of the clock and its immediate downstream targets is increased by temporally restricted feeding. The expression of BAF60a itself is not altered by food signals, 24 but it is a clock target that modulates the expression of food-driven metabolic genes, such as PEPCK and Cpt1a.…”

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).…”