Circadian misalignment has deleterious effects on metabolism, and contributes to the obesity and diabetes epidemics in the US. The nuclear receptor Rev-erb? is a transcriptional link between the circadian clock and metabolism, and the present proposal combines tissue-specific, genome-wide analyses of cistromes, transcriptomes, and the epigenome of novel mouse genetic models with sophisticated metabolic phenotyping to understand the physiological role of Rev-erb? in the coordination of circadian rhythms and metabolism.
Specific Aim 1 focuses on the role of Rev-erb? in the regulation of hepatic circadian rhythms and metabolism. Genome-wide approaches and deep metabolic phenotyping will test the hypothesis that Rev-erb? controls these processes in a cell- autonomous manner. The effects of gain and loss of function will be compared with loss of DNA binding to understand the spectrum of Rev-erb? action in liver.
Specific Aim 2 is to determine the role of brown adipose tissue Rev-erb? in the regulation of circadian rhythms and metabolism. The effects of loss of Rev-erb? in brown adipose tissue (BAT) on energy metabolism will be assessed, and compared with BAT deletion of the epigenomic modulator HDAC3, a component of the nuclear receptor corepressor complex whose effects on BAT function are paradoxically opposite to those of Rev-erb?. Genomic discovery methods will be used to understand the mechanisms by which Rev- erb? and HDAC3 work in opposition to regulate BAT metabolism, while working together to regulate the BAT molecular clock.
In Aim 3, we will determine the epigenomic functions of Rev-erb? in the architecture of chromatin, studying the mouse liver to test the hypothesis that Rev-erb? exerts its control over rhythmic gene expression and metabolic physiology in vivo by governing the promoter looping of the circadian enhancers that it controls. These studies will provide a deep understanding of how Rev-erb? acts in the genome to modulate chromatin structure and how that impacts circadian rhythmicity of gene regulation. Together, the integrative studies proposed here will lead to a more fundamental understanding of the links between circadian rhythm and metabolism that underly the mechanisms by which circadian misalignment exacerbates metabolic dysfunction, obesity, and diabetes.
Obesity, diabetes, and related metabolic diseases are rampant in the United States due to environmental challenges that include fattening diets, lack of physical exercise, as well as chronic light exposure and rotating shift work. The innovative studies proposed here explore the relationship between biological clocks and metabolic physiology, to understand how altered circadian rhythms produce metabolic disease. This work has the potential to lead to new strategies to reduce the burden of obesity and diabetes in modern society.
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