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

Rosa Martin-Mateos, Thiago M. De Assuncao, Juan Pablo Arab, Nidhi Jalan-Sakrikar, Usman Yaqoob, Thomas Greuter, Vikas K. Verma, Angela J. Mathison, Sheng Cao, Gwen Lomberk, Philippe Mathurin, Raul Urrutia, Robert C Huebert, Vijay Shah

Research output: Contribution to journalArticle

Abstract

Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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)

LanguageEnglish (US)
Pages197-209
Number of pages13
JournalCMGH
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Hepatic Stellate Cells
Liver Cirrhosis
Transforming Growth Factor beta
Platelet-Derived Growth Factor
Carbon Tetrachloride
Bile Ducts
Fibronectins
Epigenomics
Ligation
Smooth Muscle
Actins
Collagen
RNA Sequence Analysis
Enhancer of Zeste Homolog 2 Protein
Messenger RNA
Proteins
Myofibroblasts
Hydroxyproline
Small Interfering RNA
Fibrosis

Keywords

  • Epigenetics
  • EZH2
  • Histone Modifications
  • Liver Fibrosis

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Martin-Mateos, R., De Assuncao, T. M., Arab, J. P., Jalan-Sakrikar, N., Yaqoob, U., Greuter, T., ... Shah, V. (2019). Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis. CMGH, 7(1), 197-209. https://doi.org/10.1016/j.jcmgh.2018.09.005

Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis. / Martin-Mateos, Rosa; De Assuncao, Thiago M.; Arab, Juan Pablo; Jalan-Sakrikar, Nidhi; Yaqoob, Usman; Greuter, Thomas; Verma, Vikas K.; Mathison, Angela J.; Cao, Sheng; Lomberk, Gwen; Mathurin, Philippe; Urrutia, Raul; Huebert, Robert C; Shah, Vijay.

In: CMGH, Vol. 7, No. 1, 01.01.2019, p. 197-209.

Research output: Contribution to journalArticle

Martin-Mateos, R, De Assuncao, TM, Arab, JP, Jalan-Sakrikar, N, Yaqoob, U, Greuter, T, Verma, VK, Mathison, AJ, Cao, S, Lomberk, G, Mathurin, P, Urrutia, R, Huebert, RC & Shah, V 2019, 'Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis', CMGH, vol. 7, no. 1, pp. 197-209. https://doi.org/10.1016/j.jcmgh.2018.09.005
Martin-Mateos R, De Assuncao TM, Arab JP, Jalan-Sakrikar N, Yaqoob U, Greuter T et al. Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis. CMGH. 2019 Jan 1;7(1):197-209. https://doi.org/10.1016/j.jcmgh.2018.09.005
Martin-Mateos, Rosa ; De Assuncao, Thiago M. ; Arab, Juan Pablo ; Jalan-Sakrikar, Nidhi ; Yaqoob, Usman ; Greuter, Thomas ; Verma, Vikas K. ; Mathison, Angela J. ; Cao, Sheng ; Lomberk, Gwen ; Mathurin, Philippe ; Urrutia, Raul ; Huebert, Robert C ; Shah, Vijay. / Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis. In: CMGH. 2019 ; Vol. 7, No. 1. pp. 197-209.
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AU - Arab, Juan Pablo

AU - Jalan-Sakrikar, Nidhi

AU - Yaqoob, Usman

AU - Greuter, Thomas

AU - Verma, Vikas K.

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AU - Cao, Sheng

AU - Lomberk, Gwen

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