Titre :

Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-? Dependent Hepatic Stellate Cell Activation and Liver Fibrosis.

Auteur(s) :

Martin-Mateos, Rosa [Auteur]
De Assuncao, Thiago M [Auteur]
Arab, Juan Pablo [Auteur]
Jalan-Sakrikar, Nidhi [Auteur]
Yaqoob, Usman [Auteur]
Greuter, Thomas [Auteur]
Verma, Vikas K [Auteur]
Mathison, Angela J [Auteur]
Cao, Sheng [Auteur]
Lomberk, Gwen [Auteur]
Mathurin, Philippe [Auteur]
Lille Inflammation Research International Center - U 995 [LIRIC]
Urrutia, Raul [Auteur]
Huebert, Robert C [Auteur]
Shah, Vijay H. [Auteur]

Titre de la revue :

Cellular and Molecular Gastroenterology and Hepatology

Nom court de la revue :

Cell Mol Gastroenterol Hepatol

Numéro :

7

Pagination :

197-209

Date de publication :

2019

ISSN :

2352-345X

Mot(s)-clé(s) en anglais :

Liver Fibrosis
Histone Modifications
Epigenetics
EZH2

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

Transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis of liver fibrosis. Transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) are canonical ...
Lire la suite >Transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis of liver fibrosis. Transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) are canonical HSC activators after liver injury. The aim of this study was to analyze the epigenetic modulators that differentially control TGF-β and PDGF signaling pathways. We performed a transcriptomic comparison of HSCs treated with TGF-β or PDGF-BB using RNA sequencing. Among the targets that distinguish these 2 pathways, we focused on the histone methyltransferase class of epigenetic modulators. Enhancer of zeste homolog 2 (EZH2) was expressed differentially, showing significant up-regulation in HSCs activated with TGF-β but not with PDGF-BB. Indeed, EZH2 inhibition using either a pharmacologic (GSK-503) or a genetic (small interfering RNA) approach caused a significant attenuation of TGF-β-induced fibronectin, collagen 1α1, and α-smooth muscle actin, both at messenger RNA and protein levels. Conversely, adenoviral overexpression of EZH2 in HSCs resulted in a significant stimulation of fibronectin protein and messenger RNA levels in TGF-β-treated cells. Finally, we conducted in vivo experiments with mice chronically treated with carbon tetrachloride or bile duct ligation. Administration of GSK-503 to mice receiving either carbon tetrachloride or bile duct ligation led to attenuated fibrosis as assessed by Trichrome and Sirius red stains, hydroxyproline, and α-smooth muscle actin/collagen protein assays. TGF-β and PDGF share redundant and distinct transcriptomic targets, with the former predominating in HSC activation. The EZH2 histone methyltransferase is preferentially involved in the TGF-β as opposed to the PDGF signaling pathway. Inhibition of EZH2 attenuates fibrogenic gene transcription in TGF-β-treated HSCs and reduces liver fibrosis in vivo. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE119606 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119606).Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

CHU Lille
Inserm
Université de Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286

Date de dépôt :

2019-10-22T08:16:28Z
2023-12-05T13:26:57Z