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CCAAT/enhancer binding protein-mediated regulation of TGFβ receptor 2 expression determines the hepatoblast fate decision.
- Source :
-
Development (Cambridge, England) [Development] 2014 Jan; Vol. 141 (1), pp. 91-100. Date of Electronic Publication: 2013 Nov 27. - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
CCAAT-Enhancer-Binding Protein-alpha biosynthesis
CCAAT-Enhancer-Binding Protein-beta biosynthesis
Cell Differentiation
Cell Lineage
Cells, Cultured
Embryonic Stem Cells cytology
Embryonic Stem Cells metabolism
Gene Expression Regulation, Developmental
Humans
Liver embryology
Liver growth & development
Liver metabolism
Mice
Promoter Regions, Genetic genetics
Protein Serine-Threonine Kinases biosynthesis
Protein Serine-Threonine Kinases genetics
Receptor, Transforming Growth Factor-beta Type II
Receptors, Transforming Growth Factor beta biosynthesis
Receptors, Transforming Growth Factor beta genetics
Signal Transduction
Transcription, Genetic
Transforming Growth Factor beta metabolism
CCAAT-Enhancer-Binding Protein-alpha metabolism
CCAAT-Enhancer-Binding Protein-beta metabolism
Hepatocytes metabolism
Protein Serine-Threonine Kinases metabolism
Receptors, Transforming Growth Factor beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9129
- Volume :
- 141
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Development (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 24284203
- Full Text :
- https://doi.org/10.1242/dev.103168