Defining the role of non-clock genes in circadian physiology and pathophysiology

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Project Abstract Circadian misalignment is a risk factor for many diseases, such as type-2 diabetes, cardiovascular disease, hypertension, and cancer. The concept of chronotherapy is attracting more and more attention to improving drug efficacy and diminishing drug toxicity when drugs are provided at the optimized time of the day. The underlying molecular mechanism of circadian rhythm includes the interlocking positive and negative feedback loops of core clock molecular genes. In my previous study, supported by an F32 post-doctoral training grant from NIDDK, we observed circadian enhancer and transcriptome remodeling is independent of the circadian expression of core clock genes in diet-induced obesity (DIO) mice. In our new adult hepatocyte-specific REV-ERB knockout mice model and time-restricted feeding mouse, we also observed similar core clock gene-independent transcriptomic remodeling. These observations set a foundation of this K01 application and lead us to hypothesize that non- core clock genes play an essential role in the regulation of circadian enhancer activity and gene expression in various normal physiology as well as the pathophysiology of metabolic diseases. The goal of this proposal is to establish the connection of circadian epigenomic remodeling and environmental challenge and to identify and characterize non-core clock circadian regulators that can apply to chrono-pharmacological and chrono-nutritive strategies relating to metabolic diseases. To accomplish this goal, I plan to utilize unbiased genome-wide transcriptional and bioinformatics methods to map enhancer landscape and identify regulatory transcription factors (TFs) for circadian remodeling in non-hepatocytes from adult hepatocyte-specific REV-ERB (Aim 1) and also in livers of ad libitum feeding and time-restricted feeding mice (Aim 2). Actually, our unbiased whole genome- wide enhancer mapping and transcriptome analysis revealed a DIO-selective circadian transcription factor, Estrogen Related Receptor Gamma (ERRγ). Moreover, our unbiased transcriptome profiling revealed that the expression of ERRγ is markedly higher in the livers of 129S1/SvImJ (129) mice. Of note, 129 mice are highly resistant to gaining weight and developing metabolic dysfunction on diets that produce DIO in B6 mice. As a proof-of-concept study, we will determine the role of hepatic ERRγ in strain-specific response to DIO and extend our circadian rhythm study to a strain-specific context (Aim 3). Under the mentorship of Dr. Mitch Lazar, I have strengthened my training in the transcriptional regulation of hepatic metabolism. In this K01 award period, with primary mentorship from Dr. Lazar and the guidance of my advisory committee, I will extend my training on transcription regulation of metabolism to cell-cell crosstalk level (single-nuclei seq) and gain experiences about characterization of non-core clock genes in circadian physiology and pathophysiology. This training will allow me to systemically, quantitatively and functionally study molecular connections involved in metabolism. My progress in science and career development will be under supervision of my advisory committee for the transition from a postdoctoral trainee to an independent investigator.