Expression of HNF4α isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3′ end splicing
Open accessAbstract
Hepatocyte nuclear factor 4alpha (HNF4alpha) is essential for the establishment and maintenance of liver-specific gene expression. The HNF4alpha gene codes for several isoforms whose developmental and physiological relevance has not yet been explored. HNF4alpha1 and HNF4alpha7 originate from different promoters, while alternative splicing in 3' leads to HNF4alpha2 and HNF4alpha8, respectively. HNF4alpha7/alpha8 were abundantly expressed in embryonic liver and fetal-like hepatoma cells. HNF4alpha1/alpha2 transcripts were up-regulated at birth and represented the only isoforms in adult-like hepatoma cells. In line with its expression profile, HNF4alpha7 activated more avidly than HNF4alpha1 reporter plasmids for genes that are expressed early. The expression patterns of both isoforms together with the differences observed in their transcriptional activities provide elements accounting for fine-tuning of the activity of HNF4alpha. The sequential expression of HNF4alpha7/alpha8 and HNF4alpha1/alpha2 during mouse liver development is the only modification in liver-enriched transcription factors thus far recorded, which parallels the transition from the fetal to the adult hepatic phenotype.
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Only minor contributions from the Hnf4a P2 promoter were detected.
“Furthermore, we detected only minor contributions from the Hnf4a P2 promoter (Figure S4; Torres-Padilla et al., 2001).”
From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Torres-Padilla et al., 2001
The Discussion reports near-total loss of the HNF4α7 isoform associated with the P2 promoter in adult mouse liver, consistent with a minor P2 contribution there. It also reports abundant HNF4α7 in embryonic and early fetal liver, so the source does not support an unqualified claim that P2 contributions are only minor. The citing authors’ own detection in Figure S4 is not a result this source can verify. (LLM, conf=0.82)
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Cites
SRC-1 and GRIP1 Coactivate Transcription with Hepatocyte Nuclear Factor 4
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Sandovici, I., Smith, N. H., Nitert, M. D., Ackers-Johnson, M., Uribe-Lewis, S., Ito, Y., Jones, R. H., Marquez, V. E., Cairns, W., Tadayyon, M., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019007108 · Cited by 326 · see citing works
HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer
Chang, H. R., Nam, S., Kook, M.-C., Kim, K.-T., Liu, X., Yao, H., Jung, H. R., Lemos, R., Seo, H. H., Park, H. S., et al. (2016) · Gut · doi:10.1136/gutjnl-2014-307918 · Cited by 119 · see citing works
Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation
Alder, O., Cullum, R., Lee, S., Kan, A. C., Wei, W., Yi, Y., Garside, V. C., Bilenky, M., Griffith, M., Morrissy, A. S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.046 · Cited by 113 · see citing works
“Furthermore, we detected only minor contributions from the Hnf4a P2 promoter (Figure S4; Torres-Padilla et al., 2001).”
BackgroundNg, N. H. J., Ghosh, S., Bok, C. M., Ching, C., Low, B. S. J., Chen, J. T., Lim, E., Miserendino, M. C., Tan, Y. S., Hoon, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48647-w · Cited by 57 · see citing works
Beaudry, J.-B., Pierreux, C. E., Hayhurst, G. P., Plumb-Rudewiez, N., Weiss, M. C., Rousseau, G. G., & Lemaigre, F. P. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02445-05 · Cited by 56 · see citing works
Self-citation
- Authors
- Torres-Padilla, M. E., Fougère-Deschatrette, C., & Weiss, M. C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Weiss, Mary C
- Venue
- Mechanisms of Development
- Publisher
- Elsevier BV
- Published
- 2001-12
- Volume
- 109
- Issue
- 2
- Pages
- 183-193
- ISSN
- 0925-4773 (ISSN-L)
- OpenAlex
- W2023723464
- Cited by
- 96
- References
- 1
- Citations by year
- 2025: 5 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 6 · 2014: 5 · 2012: 4
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Mechanisms of Development (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- Consejo Nacional de Ciencia y Tecnología
- 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 › RNA Research and Splicing
- Keywords
- HNF4α, protein isoforms, liver development, promoter usage, alternative splicing, embryonic liver, hepatocyte nuclear factor, transcriptional activity, liver-specific gene expression, hepatoma cells
- MeSH terms
- Animals, Cell Line, DNA-Binding Proteins, Exons, Carcinoma, Hepatocellular, Liver, Models, Genetic, Phenotype, Phosphoproteins, Plasmids, Promoter Regions, Genetic, RNA Splicing, RNA, Messenger, Time Factors, Transcription Factors, Transcription, Genetic, Transfection, Blotting, Northern, Blotting, Western, Transcriptional Activation, 3T3 Cells, Alternative Splicing, Genes, Reporter, Dimerization, Protein Isoforms, Reverse Transcriptase Polymerase Chain Reaction, Mice, Hepatocyte Nuclear Factor 4, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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