The identification and characterization of a novel circadian ETS factor

University Of Pennsylvania, Philadelphia PA

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Abstract

Project Summary This application is for a predoctoral fellowship awarded by the National Institute of Diabetes and Digestive and Kidney Diseases to physician-scientist trainees. The applicant is a trainee of the Medical Scientist Training Program at the Perelman School of Medicine at the University of Pennsylvania. This award would help him achieve his career goal of becoming a physician-scientist investigating the role of circadian rhythms in metabolism. Circadian rhythms are biological clocks that regulate all-encompassing aspects of human physiology. Circadian misalignment is prevalent in the modern society and one of the contributing factors to the rising epidemics of obesity and diabetes in the U.S. and worldwide. In support of this, many epidemiological studies have demonstrated that night shift workers are more likely to have higher BMI and more prone to developing metabolic diseases such as obesity, diabetes, and related cardiovascular comorbidities. While this is an imperative public health issue with increasing significance, we still lack a mechanistic understanding of the relationship between the circadian clock and metabolism. In efforts to better understand the molecular mechanisms linking circadian rhythms to metabolic homeostasis, our lab has undertaken a genome-wide study characterizing how hepatic transcription is regulated in a circadian manner. Reassuringly, we identified several transcription factors known to coordinate specific circadian phases of transcription, such as Rev-erb? and Bmal1. Interestingly, our functional genomic data predicted that a transcription factor from the ETS family regulates a circadian phase of transcription at 7 AM-10 AM. However, there is no ETS factor known to behave in a circadian manner. In this proposal, I provide preliminary proteomic and genomic data suggesting that GABP? is the circadian ETS transcription factor, with potential roles in mitochondrial biogenesis and metabolic homeostasis. This finding raises both mechanistic questions about how GABP? coordinates circadian transcription and the functional role of GABP? in hepatic metabolism. For Aim 1, I will dissect the molecular mechanism of circadian transcriptional control by GABP? using a genetic loss-of-function approach and an unbiased proteomics approach. For Aim 2, I will determine the physiological role of GABP? in hepatic metabolism by measuring physiologic and metabolic parameters and performing functional metabolic assays, ultimately to link molecular, cellular, and metabolic changes with physiological outcomes. These integrative experiments will determine the previously unrecognized circadian role of GABP? in transcriptional regulation and hepatic metabolism. Furthermore, the novel insights gained from this proposal will have both mechanistic and therapeutic implications for how circadian misalignment leads to metabolic dysfunction.