Abstract
Metabolic adaptation to nutritional state requires alterations in gene expression in key tissues. Here, we investigated chromatin interaction dynamics, as well as alterations in cis-regulatory loci and transcriptional network in a mouse model system. Chronic consumption of a diet high in saturated fat, when compared to a diet high in carbohydrate, led to dramatic reprogramming of the liver transcriptional network. Long-range interaction of promoters with distal regulatory loci, monitored by promoter capture Hi-C, was regulated by metabolic status in distinct fashion depending on diet. Adaptation to a lipid-rich diet, mediated largely by nuclear receptors including Hnf4α, relied on activation of preformed enhancer/promoter loops. Adaptation to carbohydrate-rich diet led to activation of preformed loops and to de novo formation of new promoter/enhancer interactions. These results suggest that adaptation to nutritional changes and metabolic stress occurs through both de novo and pre-existing chromatin interactions which respond differently to metabolic signals.
Highlights
Metabolic adaptation to nutritional state requires alterations in gene expression in key tissues
To date, limited data are available describing the dynamics of promoter–enhancer interactions during metabolic adaptation to changes in diet and progression to overt physiologic changes leading to disease and how these processes impact gene expression
To model the gene regulatory events associated with metabolic adaptation to chronic obesity and nonalcoholic fatty liver disease (NAFLD), we performed diet studies on male C57BL/6 mice (Fig. 1a)
Summary
Metabolic adaptation to nutritional state requires alterations in gene expression in key tissues. These physiologic states have differing homeostatic requirements ranging from the mobilization of storage depots that provide energy and critical biomolecules to the biosynthesis of molecules mediating deposition of energy and metabolic precursors, with accompanying alterations in gene expression programs to facilitate biological responses Such metabolic adaptation can lead, in the extreme, to the development and progression of obesity and related diseases including nonalcoholic fatty liver disease (NAFLD)[1,2]. To date, limited data are available describing the dynamics of promoter–enhancer interactions during metabolic adaptation to changes in diet and progression to overt physiologic changes leading to disease and how these processes impact gene expression Given this dearth of information, a deeper understanding of the how the liver epigenome responds to diet, obesity, and the dysfunctional metabolic and physiologic state associated with obesity should provide insights into adaptation and disease. These findings provide insights into how chromatin organization contributes to gene regulation during metabolic adaptation and disease
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