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

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          Abstract

          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.

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          Most cited references36

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          The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors.

          Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role of EZH2 in tumorigenesis in vivo remains poor, in particular in metastasizing solid cancers. Here we reveal central roles of EZH2 in promoting growth and metastasis of cutaneous melanoma. In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical EZH2 inhibitor GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology. Comparably, in human melanoma cells, EZH2 inactivation impairs proliferation and invasiveness, accompanied by re-expression of tumour suppressors connected to increased patient survival. These EZH2 target genes suppress either melanoma growth or metastasis in vivo, revealing the dual function of EZH2 in promoting tumour progression. Thus, EZH2-mediated epigenetic repression is highly relevant especially during advanced melanoma progression, which makes EZH2 a promising target for novel melanoma therapies.
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            Polycomb group protein ezh2 controls actin polymerization and cell signaling.

            Polycomb group protein Ezh2, one of the key regulators of development in organisms from flies to mice, exerts its epigenetic function through regulation of histone methylation. Here, we report the existence of the cytosolic Ezh2-containing methyltransferase complex and tie the function of this complex to regulation of actin polymerization in various cell types. Genetic evidence supports the essential role of cytosolic Ezh2 in actin polymerization-dependent processes such as antigen receptor signaling in T cells and PDGF-induced dorsal circular ruffle formation in fibroblasts. Revealed function of Ezh2 points to a broader usage of lysine methylation in regulation of both nuclear and extra-nuclear signaling processes.
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              Is Open Access

              Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis

              In most vertebrates, the liver produces bile that is necessary to emulsify absorbed fats and enable the digestion of lipids in the small intestine as well as to excrete bilirubin and other metabolic products. In the liver, the experimental obstruction of the extrahepatic biliary system initiates a complex cascade of pathological events that leads to cholestasis and inflammation resulting in a strong fibrotic reaction originating from the periportal fields. Therefore, surgical ligation of the common bile duct has become the most commonly used model to induce obstructive cholestatic injury in rodents and to study the molecular and cellular events that underlie these pathophysiological mechanisms induced by inappropriate bile flow. In recent years, different surgical techniques have been described that either allow reconnection or reanastomosis after bile duct ligation (BDL), e.g., partial BDL, or other microsurgical methods for specific research questions. However, the most frequently used model is the complete obstruction of the common bile duct that induces a strong fibrotic response after 21 to 28 days. The mortality rate can be high due to infectious complications or technical inaccuracies. Here we provide a detailed surgical procedure for the BDL model in mice that induce a highly reproducible fibrotic response in accordance to the 3R rule for animal welfare postulated by Russel and Burch in 1959.
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                Author and article information

                Journal
                Cell Mol Gastroenterol Hepatol
                Cellular and molecular gastroenterology and hepatology
                Elsevier BV
                2352-345X
                2352-345X
                2019
                : 7
                : 1
                Affiliations
                [1 ] Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Ramón y Cajal University Hospital, Madrid, Spain.
                [2 ] Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
                [3 ] Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile.
                [4 ] Genomics and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
                [5 ] Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
                [6 ] Service Maladie de l'Appareil Digestif, INSERM U995 Université Lille 2, Centre Hospitalier Régionale Universitaire (CHRU) de Lille, France.
                [7 ] Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: shah.vijay@mayo.edu.
                Article
                S2352-345X(18)30127-9
                10.1016/j.jcmgh.2018.09.005
                6282644
                30539787
                97eae482-01c3-4408-951e-fed1a1cbae21
                Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
                History

                EZH2,Epigenetics,Histone Modifications,Liver Fibrosis
                EZH2, Epigenetics, Histone Modifications, Liver Fibrosis

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