Identification of super-enhancers regulatory network mediates the pathogenesis of hyperlipidemia

Abstract

Abstract Hyperlipidemia (HLP) is a prevalent metabolic disorder and a significant risk factor for cardiovascular disease. According to recent discoveries, super-enhancers (SEs) play a role in the increased expression of genes that encode important regulators of both cellular identity and the progression of diseases. However, the underlying function of SEs in the development of HLP is still unknown. We performed an integrative analysis of H3K27ac ChIP-seq data and RNA-seq data obtained from liver tissues of mice under a low-fat diet (LFD) and high-fat diet (HFD) from the GEO database. The rank ordering of super enhancers algorithm was employed for the computation and identification of SEs. A total of 1877 and 1847 SEs were identified in the LFD and HFD groups, respectively. The SE inhibitor JQ1 was able to potently reverse lipid deposition and the increased intracellular triglyceride and total cholesterol induced by oleic acid (OA), indicating that SEs are involved in regulating lipid accumulation. Among the identified SEs, 278 were considered as HFD-specific SEs (HSEs). Gene Ontology and KEGG pathway enrichment analysis of HSEs-associated genes revealed that they are mainly involved in lipid metabolism and transcription regulation. Tsku was a highly ranked HSEs-associated differentially expressed genes. JQ1 reversed the elevated Tsku mRNA level induced by OA treatment, whereas there was no significantly change with JQ1 alone. The results above indicate that the HSE regulatory network is involved in the pathogenesis of HLP, suggesting that it could be a promising target for future treatments for HLP.