Date of Award
Master of Science in Pharmaceutical Sciences
Biomedical and Pharmaceutical Sciences
Circadian rhythms ensure physiological processes to be coordinated with daily changes of the surrounding. Circadian rhythm misalignment has been increasingly recognized to pose health risk for a wide range of diseases, particularly metabolic disorders. The liver maintains metabolic homeostasis and express many circadian genes, such as the genes encoding differentiated embryo chondrocyte-1 (DEC1) and small heterodimer partner (SHP). DEC1 is established to repress transcription through class B E-box elements, and SHP belongs to the superfamily of nuclear receptors and has multiple Ebox elements in its promoter. Importantly, DEC1 and SHP are expressed in an inverse oscillating manner. The present study was performed to test the hypothesis that the SHP gene is a target gene of DEC1. In cotransfection experiments, we have demonstrated that DEC1 repressed the SHP promoter and attenuated the transactivation of the classic circadian activator complex of Clock/Bmal1. Site-directed mutagenesis, electrophoretic mobility shift assay and chromatin immunoprecipitation established that the repression was achieved through the E-box in the proximal promoter. Overexpression of DEC1 led to decreased expression of SHP. In horse serum-shocked cells (induction of circadian rhythms), the widely used epileptic agent valproate inversely altered the expression of DEC1 and SHP. Both DEC1 and SHP are involved in energy balance and valproate is known to induce hepatic steatosis. Our findings collectively establish that DEC1 constitutes the negative loop of the SHP oscillating expression and that the DEC1-SHP pathway is intimately involved in energy homeostasis with profound pathophysiologic significance.
Marczak, Marek Matczynski, "Circadian Rhythm: A Functional Connection Between SHP and DEC1 Transcription Factor" (2017). Open Access Master's Theses. Paper 1092.
Available for download on Wednesday, October 16, 2019