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

Nat Commun. 2021 Jul 27;12(1):4560. doi: 10.1038/s41467-021-24843-w.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chemokines / biosynthesis*
  • Cytokines / pharmacology*
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Enhancer Elements, Genetic*
  • Epigenesis, Genetic / drug effects
  • Gene Expression Regulation / drug effects
  • Hepatitis, Alcoholic / genetics*
  • Histones / metabolism
  • Humans
  • Lipopolysaccharides
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA-Seq
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Chemokines
  • Cytokines
  • Histones
  • Lipopolysaccharides
  • NF-kappa B
  • Transcription Factors
  • Tumor Necrosis Factor-alpha