title: Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion.
abstract: OBJECTIVE
  Developmental morphogens play an important role in coordinating the ductular reaction and portal fibrosis occurring in the setting of cholangiopathies. However, little is known about how membrane signaling events in ductular reactive cells (DRCs) are transduced into nuclear transcriptional changes to drive cholangiocyte maturation and matrix deposition. Therefore, the aim of this study was to investigate potential mechanistic links between cell signaling events and epigenetic regulators in DRCs.
  
  
  METHODS
  Using directed differentiation of induced pluripotent stem cells (iPSC), isolated DRCs, and in vivo models, we examine the mechanisms whereby sonic hedgehog (Shh) overcomes an epigenetic barrier in biliary precursors and promotes both cholangiocyte maturation and deposition of fibronectin (FN).
  
  
  RESULTS
  We demonstrate, for the first time, that Gli1 influences the differentiation state and fibrogenic capacity of iPSC-derived hepatic progenitors and isolated DRCs. We outline a novel pathway wherein Shh-mediated Gli1 binding in key cholangiocyte gene promoters overcomes an epigenetic barrier conferred by the polycomb protein, enhancer of zeste homolog 2 (EZH2) and initiates the transcriptional program of cholangiocyte maturation. We also define previously unknown functional Gli1 binding sites in the promoters of cytokeratin (CK)7, CK19, and FN. Our in vivo results show that EZH2 KO mice fed the choline-deficient, ethanolamine supplemented (CDE) diet have an exaggerated cholangiocyte expansion associated with more robust ductular reaction and increased peri-portal fibrosis.
  
  
  CONCLUSIONS
  We conclude that Shh/Gli1 signaling plays an integral role in cholangiocyte maturation in vitro by overcoming an EZH2-dependent epigenetic barrier and this mechanism also promotes biliary expansion in vivo.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN, United States of America.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jalan-Sakrikar
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN, United States of America.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: De Assuncao
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Schultze Center for Novel Therapeutics, Mayo Clinic and Foundation, Rochester, MN, United States of America.
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN, United States of America.
authors.forename: Gwen
authors.initials: G
authors.lastname: Lomberk
authors.affiliation: Schultze Center for Novel Therapeutics, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN, United States of America.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN, United States of America.
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN, United States of America.|Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Huebert
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000502:physiology*; D044127:Epigenesis, Genetic; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D053823:Hedgehog Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein