Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis
| Autor: | Angela Mathison, Usman Yaqoob, Juan Pablo Arab, Vikas K. Verma, Vijay H. Shah, Philippe Mathurin, Gwen Lomberk, Sheng Cao, Rosa Martin-Mateos, Robert C. Huebert, Raul Urrutia, Thomas Greuter, Thiago M. De Assuncao, Nidhi Jalan-Sakrikar |
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| Rok vydání: | 2019 |
| Předmět: |
WT
wild type Liver Cirrhosis 0301 basic medicine IP intraperitoneally Small interfering RNA PDGF platelet-derived growth factor Epigenesis Genetic PCR polymerase chain reaction 0302 clinical medicine PDGF Signaling Pathway Transforming Growth Factor beta Carbon Tetrachloride Original Research Platelet-Derived Growth Factor TGF-β transforming growth factor β Extracellular Matrix Proteins biology Chemistry EZH2 enhancer of zeste homologue 2 EZH2 Gastroenterology HSC hepatic stellate cell mRNA messenger RNA Up-Regulation ECM extracellular matrix 3. Good health Cell biology ChIP chromatin immunoprecipitation H3K27me3 trimethylation of histone 3 at lysine 27 Histone methyltransferase Liver Fibrosis Epigenetics 030211 gastroenterology & hepatology Platelet-derived growth factor receptor DKK1 Dickkopf-1 FDR false discovery rate CCL4 carbon tetrachloride BDL bile duct ligation CTGF connective tissue growth factor α-SMA α-smooth muscle actin 03 medical and health sciences VEGFA vascular endothelial growth factor A FBS fetal bovine serum Hepatic Stellate Cells Animals Humans Enhancer of Zeste Homolog 2 Protein lcsh:RC799-869 Ligation IPA Ingenuity Pathway Analysis Messenger RNA Hepatology Histone Modifications logFC logarithmic fold change Hepatic stellate cell activation Mice Inbred C57BL 030104 developmental biology siRNA small interfering RNA Hepatic stellate cell biology.protein lcsh:Diseases of the digestive system. Gastroenterology Bile Ducts HMT histone methyltransferase HCC hepatocellular carcinoma |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid Cellular and Molecular Gastroenterology and Hepatology, Vol 7, Iss 1, Pp 197-209 (2019) |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2018.09.005 |
| Popis: | 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) Graphical abstract |
| Databáze: | OpenAIRE |
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