Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis

Mengfei Liu, Sheng Cao, Li He, Jinhang Gao, Juan P. Arab, Huarui Cui, Weixia Xuan, Yandong Gao, Tejasav S. Sehrawat, Feda H. Hamdan, Meritxell Ventura-Cots, Josepmaria Argemi, William C.K. Pomerantz, Steven A. Johnsen, Jeong Heon Lee, Fei Gao, Tamas Ordog, Philippe Mathurin, Alexander Revzin, Ramon BatallerHuihuang Yan, Vijay H. Shah

Research output: Contribution to journalArticlepeer-review

Abstract

Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNFα with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNFα/NF-κB signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment.

Original languageEnglish (US)
Article number4560
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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