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 helix-loop-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.