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

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dc.contributor.authorLiu, Mengfei
dc.contributor.authorCao, Sheng
dc.contributor.authorHe, Li
dc.contributor.authorGao, Jinhang
dc.contributor.authorArab, Juan P.
dc.contributor.authorCui, Huarui
dc.contributor.authorXuan, Weixia
dc.contributor.authorGao, Yandong
dc.contributor.authorSehrawat, Tejasav S.
dc.contributor.authorHamdan, Feda H.
dc.contributor.authorVentura-Cots, Meritxell
dc.contributor.authorArgemi, Josepmaria
dc.contributor.authorPomerantz, William C. K.
dc.contributor.authorJohnsen, Steven A.
dc.contributor.authorLee, Jeong-Heon
dc.contributor.authorGao, Fei
dc.contributor.authorOrdog, Tamas
dc.contributor.authorMathurin, Philippe
dc.contributor.authorRevzin, Alexander
dc.contributor.authorBataller, Ramon
dc.contributor.authorYan, Huihuang
dc.contributor.authorShah, Vijay H.
dc.date.accessioned2025-01-20T22:14:10Z
dc.date.available2025-01-20T22:14:10Z
dc.date.issued2021
dc.description.abstractAlcoholic 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 TNF alpha 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 TNF alpha /NF-kappa B 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. Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.
dc.description.funderNational Institutes of Health (NIH), USA
dc.fuente.origenWOS
dc.identifier.doi10.1038/s41467-021-24843-w
dc.identifier.issn2041-1723
dc.identifier.urihttps://doi.org/10.1038/s41467-021-24843-w
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94472
dc.identifier.wosidWOS:000683367300023
dc.issue.numero1
dc.language.isoen
dc.revistaNature communications
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleSuper enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis
dc.typeartículo
dc.volumen12
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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