title: CCAAT/enhancer binding protein-mediated regulation of TGFβ receptor 2 expression determines the hepatoblast fate decision.
abstract: Human embryonic stem cells (hESCs) and their derivatives are expected to be used in drug discovery, regenerative medicine and the study of human embryogenesis. Because hepatocyte differentiation from hESCs has the potential to recapitulate human liver development in vivo, we employed this differentiation method to investigate the molecular mechanisms underlying human hepatocyte differentiation. A previous study has shown that a gradient of transforming growth factor beta (TGFβ) signaling is required to segregate hepatocyte and cholangiocyte lineages from hepatoblasts. Although CCAAT/enhancer binding proteins (c/EBPs) are known to be important transcription factors in liver development, the relationship between TGFβ signaling and c/EBP-mediated transcriptional regulation in the hepatoblast fate decision is not well known. To clarify this relationship, we examined whether c/EBPs could determine the hepatoblast fate decision via regulation of TGFβ receptor 2 (TGFBR2) expression in the hepatoblast-like cells differentiated from hESCs. We found that TGFBR2 promoter activity was negatively regulated by c/EBPα and positively regulated by c/EBPβ. Moreover, c/EBPα overexpression could promote hepatocyte differentiation by suppressing TGFBR2 expression, whereas c/EBPβ overexpression could promote cholangiocyte differentiation by enhancing TGFBR2 expression. Our findings demonstrated that c/EBPα and c/EBPβ determine the lineage commitment of hepatoblasts by negatively and positively regulating the expression of a common target gene, TGFBR2, respectively.
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takayama
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawabata
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nagamoto
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Inamura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohashi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okuno
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Tashiro
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sakurai
authors.forename: Takao
authors.initials: T
authors.lastname: Hayakawa
authors.forename: Teruo
authors.initials: T
authors.lastname: Okano
authors.forename: Miho Kusada
authors.initials: MK
authors.lastname: Furue
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: CEBP; Hepatoblasts; Human ESCs; c/EBP