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Super Enhancer Regulation of Cytokine-Induced Chemokine Production in Alcoholic Hepatitis [ChIP-Seq]

ABSTRACT: We performed histone modification ChIP-Seq in human liver explants and showed upregulation of multiple CXCL chemokines in AH. ChIP-Seq, chromosome conformation capture assays, and in silico analysis of published data identified a super enhancer for multiple CXCL genes. Targeting this super enhancer by dCas9-KRAB-mediated epigenome editing and Bromodomain and Extraterminal (BET) inhibitors decreased the expression of multiple CXCL genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155908 | GEO | 2020/10/19

REPOSITORIES: GEO

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Project description:BACKGROUND: Alcohol-related liver disease ranges from silent alcoholic steatohepatitis (sASH), an asymptomatic and compensated phenotype, to life- threatening alcoholic hepatitis (AH). A systematic comparative study of the clinical, histological and molecular features of these subtypes is lacking. METHODS : Two large cohorts of patients were recruited in an international, observational multi-center study: a retrospective cohort of patients with sASH (n=110) and a prospective cohort of patients with AH (two subgroups with n=121 and 104). sASH and AH were compared by doing clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis. FINDINGS: Age and mean alcohol intake were similar in patients with sASH vs AH. AH showed lower mean arterial pressure than sASH. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma- glutamyl transferase levels than AH. Individuals with AH demonstrated profound liver failure, lower blood pressure and increased mortality. Histologically, the grade of steatosis, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and progenitor cell expansion were more frequent among AH patients. One-year mortality was 10% in sASH and 50% in AH. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. Globally, AH patients exhibited changes in 4,921 genes, while the number of dysregulated genes in sASH patients was less pronounced -1,327-. While sASH was characterized by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. INTERPRETATION: Despite comparable daily alcohol intake, AH patients presented with worse liver function and hemodynamic status compared to sASH. Bilirubinostasis, severe fibrosis and progenitor cell expansion were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared to sASH.

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Super Enhancer Regulation of Cytokine-Induced Chemokine Production in Alcoholic Hepatitis [ChIP-Seq]

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