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Skeletal muscle enhancer interactions identify genes controlling whole body metabolism in humans [cHiC-seq]

ABSTRACT: Obesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors, and characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority is located in non-coding DNA regions. This suggest that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNFα. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism and linked to SNPs associated with the development of obesity and T2D.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126100 | GEO | 2020/03/26

REPOSITORIES: GEO

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Project description:Physical inactivity and western diet are the main factors leading to skeletal muscle (and whole-body) insulin resistance – a defect in insulin-mediated glucose uptake and metabolism – and associated metabolic diseases, such as obesity and type 2 diabetes mellitus (T2D). The study of the response to a mixed meal (normalized for body mass and/or basal metabolic rate) is of particular interest, as it simulates the physiological response to a typical (daily) single meal that depends on both the secretory function of the beta cells (insulin response) and the sensitivity of skeletal muscle signaling to insulin – variables, which markedly changing during development of insulin resistance and T2D. We aimed to compare the early transcriptomic response to a mixed meal normalized to body mass in skeletal muscle of healthy subjects and obese patients without (Ob) and with T2D (Ob+T2D). To investigate the early transcriptomic response we took biopsy samples from the vastus lateralis muscle prior to and 1 h after a meal. In the Ob+T2D group the average level and increase in C-peptide and insulin in the blood were comparable with healthy subjects that, apparently, is explained by dysfunction of the beta-cells induced by chronic T2D. At the same time, the Ob+T2D group demonstrated dysregulation of mixed meal-induced gene expression in skeletal muscle: morу than two times lower number of DEGs and a small overlapping with the gene response in the control group. On the contrary, the postprandial level of C-peptide and insulin in the Ob group was significantly greater than in healthy control that is related to insulin oversecretion associated with insulin resistance. Despite this, the gene response in skeletal muscle was also significantly dysregulated; moreover, it differed from the response in the Ob+T2D group. It means that defect in regulation of insulin-induced gene expression (insulin resistance in terms of gene expression) appears at the first stage of the development of metabolic disorders.

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Skeletal muscle enhancer interactions identify genes controlling whole body metabolism in humans [cHiC-seq]

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