Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis.
Animals
Chemokines
/ biosynthesis
Cytokines
/ pharmacology
Disease Models, Animal
Endothelial Cells
/ drug effects
Enhancer Elements, Genetic
Epigenesis, Genetic
/ drug effects
Gene Expression Regulation
/ drug effects
Hepatitis, Alcoholic
/ genetics
Histones
/ metabolism
Humans
Lipopolysaccharides
Liver
/ drug effects
Mice, Inbred C57BL
NF-kappa B
/ metabolism
Neutrophils
/ drug effects
Promoter Regions, Genetic
/ genetics
RNA-Seq
Signal Transduction
/ drug effects
Transcription Factors
/ metabolism
Tumor Necrosis Factor-alpha
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 07 2021
27 07 2021
Historique:
received:
30
05
2020
accepted:
01
07
2021
entrez:
28
7
2021
pubmed:
29
7
2021
medline:
5
8
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34315876
doi: 10.1038/s41467-021-24843-w
pii: 10.1038/s41467-021-24843-w
pmc: PMC8316465
doi:
Substances chimiques
Chemokines
0
Cytokines
0
Histones
0
Lipopolysaccharides
0
NF-kappa B
0
Transcription Factors
0
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4560Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK084567
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA021171
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK059615
Pays : United States
Informations de copyright
© 2021. The Author(s).
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