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 Bataller, Huihuang Yan () and Vijay H. Shah ()
Additional contact information
Mengfei Liu: Mayo Clinic
Sheng Cao: Mayo Clinic
Li He: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Jinhang Gao: West China Hospital, Sichuan University
Juan P. Arab: School of Medicine of the Pontificia Universidad Católica de Chile
Huarui Cui: University of Minnesota
Weixia Xuan: Henan Provincial People’s Hospital
Yandong Gao: Mayo Clinic
Tejasav S. Sehrawat: Mayo Clinic
Feda H. Hamdan: Mayo Clinic
Meritxell Ventura-Cots: University of Pittsburgh
Josepmaria Argemi: University of Pittsburgh
William C. K. Pomerantz: University of Minnesota
Steven A. Johnsen: Mayo Clinic
Jeong-Heon Lee: Mayo Clinic
Fei Gao: Mayo Clinic
Tamas Ordog: Mayo Clinic
Philippe Mathurin: University of Lille
Alexander Revzin: Mayo Clinic
Ramon Bataller: University of Pittsburgh
Huihuang Yan: Mayo Clinic
Vijay H. Shah: Mayo Clinic

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24843-w

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DOI: 10.1038/s41467-021-24843-w

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