Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1α Are Required for Time-Specific Gene Expression during Liver Development
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During liver development, hepatocytes undergo a maturation process that leads to the fully differentiated state. This relies at least in part on the coordinated action of liver-enriched transcription factors (LETFs), but little is known about the dynamics of this coordination. In this context we investigate here the role of the LETF hepatocyte nuclear factor 6 (HNF-6; also called Onecut-1) during hepatocyte differentiation. We show that HNF-6 knockout mouse fetuses have delayed expression of glucose-6-phosphatase (g6pc), which catalyzes the final step of gluconeogenesis and is a late marker of hepatocyte maturation. Using a combination of in vivo and in vitro gain- and loss-of-function approaches, we demonstrate that HNF-6 stimulates endogenous g6pc gene expression directly via a synergistic and interdependent action with HNF-4 and that it involves coordinate recruitment of the coactivator PGC-1alpha. The expression of HNF-6, HNF-4, and PGC-1alpha rises steadily during liver development and precedes that of g6pc. We provide evidence that threshold levels of HNF-6 are required to allow synergism between HNF-6, HNF-4, and PGC-1alpha to induce time-specific expression of g6pc. Our observations on the regulation of g6pc by HNF-6 provide a model whereby synergism, interdependency, and threshold concentrations of LETFs and coactivators determine time-specific expression of genes during liver development.
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h-NG2/BMMSCs showed approximately 2-fold and 2.5-fold higher potential for host mature hepatocyte regeneration, as indicated by Alb and G6Pc, respectively, than parental h-BMMSCs.
“The significant potential of h-NG2/BMMSCs was also shown for host mature hepatocyte regeneration, as indicated by the presence of albumin(Alb, Fig. 6Dd, e, boxes)and G6Pc (Suppl. Fig. S3Da-c, arrows), another marker for mature hepatocytes [40], approximately 2-fold and 2.5-fold higher than that of parental h-BMMSCs, respectively (Fig. 6Df; Suppl. Fig. S3 Dd).”
From New advances of NG2-expressing cell subset in marrow mesenchymal stem cells as novel therapeutic tools for liver fibrosis/cirrhosis (2024) · cites this paper as [40]
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Strategic Replication of the Hepatic Zonation In Vitro Employing a Biomimetic Approach
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DEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER
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- Authors
- Beaudry, J.-B., Pierreux, C. E., Hayhurst, G. P., Plumb-Rudewiez, N., Weiss, M. C., Rousseau, G. G., & Lemaigre, F. P.
- Affiliations
- UCLouvain (BE)
- Institut Pasteur (FR)
- Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université Catholique de Louvain, 75 Avenue Hippocrate, B-1200 Brussels, Belgium
- Corresponding author
- Lemaigre, Frédéric P.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-08-01
- Volume
- 26
- Issue
- 16
- Pages
- 6037-6046
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2140086125
- Cited by
- 56
- References
- 52
- Citations by year
- 2025: 2 · 2024: 8 · 2023: 1 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 4 · 2013: 4 · 2012: 2
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
- Funders
- Fédération Wallonie-Bruxelles
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HNF4, PGC-1α, liver development, hepatocyte differentiation, glucose-6-phosphatase, gene expression regulation, transcriptional synergy, transcriptional coactivator, liver-enriched transcription factors, gluconeogenesis
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Base Sequence, Cell Differentiation, Cells, Cultured, Embryo, Mammalian, Glucose-6-Phosphatase, Humans, Liver, Molecular Sequence Data, Promoter Regions, Genetic, Protein Binding, RNA, Messenger, Time Factors, Transcription Factors, Trans-Activators, Mice, Knockout, Gene Expression Regulation, Developmental, Hepatocytes, NIH 3T3 Cells, Mice, Hepatocyte Nuclear Factor 4, Hepatocyte Nuclear Factor 6
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