Journal
OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY
Volume 25, Issue 10, Pages 652-659Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/omi.2021.0093
Keywords
ATAC-seq; regulatory element; T2D; liver
Funding
- SciLifeLab
- Swedish Diabetes Foundation [DIA 2017-269]
- family Ernfors Fund
- Swedish Research Council [VR-2016-06794, VR-2017-02074]
- AstraZeneca
- EXODIAB
- Swedish Research Council [2017-02074, 2016-06794] Funding Source: Swedish Research Council
- Vinnova [2017-02074] Funding Source: Vinnova
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The study integrated ATAC-seq data, multi-omics data, and CRE databases to identify candidate CREs associated with T2D, detecting differentially accessible regions in human liver samples from normal and T2D donors. A candidate enhancer for the ACOT1 gene was identified, linking its regulation to T2D. ACOTs are enzymes associated with regulation of triglyceride levels, fatty acid oxidation, mitochondrial function, and insulin signaling, with implications for T2D pathogenesis.
Type 2 diabetes (T2D) is characterized by pathophysiological alterations in lipid metabolism. One strategy to understand the molecular mechanisms behind these abnormalities is to identify cis-regulatory elements (CREs) located in chromatin-accessible regions of the genome that regulate key genes. In this study we integrated assay for transposase-accessible chromatin followed by sequencing (ATAC-seq) data, widely used to decode chromatin accessibility, with multi-omics data and publicly available CRE databases to identify candidate CREs associated with T2D for further experimental validations. We performed high-sensitive ATAC-seq in nine human liver samples from normal and T2D donors, and identified a set of differentially accessible regions (DARs). We identified seven DARs including a candidate enhancer for the ACOT1 gene that regulates the balance of acyl-CoA and free fatty acids (FFAs) in the cytoplasm. The relevance of ACOT1 regulation in T2D was supported by the analysis of transcriptomics and proteomics data in liver tissue. Long-chain acyl-CoA thioesterases (ACOTs) are a group of enzymes that hydrolyze acyl-CoA esters to FFAs and coenzyme A. ACOTs have been associated with regulation of triglyceride levels, fatty acid oxidation, mitochondrial function, and insulin signaling, linking their regulation to the pathogenesis of T2D. Our strategy integrating chromatin accessibility with DNA binding and other types of omics provides novel insights on the role of genetic regulation in T2D and is extendable to other complex multifactorial diseases.
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