Hepatocyte Nuclear Factor-4 Controls Transcription from a TATA-less Human Sex Hormone-binding Globulin Gene Promoter
Open accessAbstract
Hepatocytes are the major source of sex hormone-binding globulin (SHBG), a glycoprotein that transports sex steroids in the blood and regulates their access to target tissues. The human SHBG proximal promoter was analyzed by DNase I footprinting, and the functional significance of 6 footprinted regions (FP1-FP6) within the proximal promoter was studied in human HepG2 hepatoblastoma cells. Two footprinted regions (FP1 and FP3) contain binding sites for the chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and hepatocyte nuclear factor-4 (HNF-4). In experiments where SHBG promoter-luciferase reporter gene constructs were co-transfected into HepG2 cells with COUP-TF and/or HNF-4 expression vectors, HNF-4 markedly increased transcription, whereas COUP-TF suppressed this probably by displacing HNF-4 from their common FP1-binding site. This COUP-TF/HNF-4-binding site within FP1 includes a TTTAA sequence, located at nucleotides -30/-26 upstream of the transcription start site, which fails to interact with human TFIID, TATA-binding protein in vitro. When this sequence was replaced with an idealized HNF-4-binding site, the transcriptional activity of the promoter increased in HepG2 cells. Taken together, these data imply that an interplay between COUP-TF and HNF-4 at a site within FP1 regulates human SHBG expression and that HNF-4 controls transcription from this TATA-less promoter by somehow substituting for TATA-binding protein in the recruitment of a transcription preinitiation complex.
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The interaction between HNF-4α and COUP-TF serves as a molecular 'on-off switch' mechanism that explains the acute response of SHBG expression to changes in metabolic states.
“Their interaction serves as a molecular ‘on–off switch’ mechanism that explains the acute response of SHBG expression to changes in metabolic states [85].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [85]
The Discussion reports that HNF-4 and COUP-TF compete for a binding site in the SHBG promoter, and the promoter experiments show that COUP-TF represses HNF-4-driven transcription. This supports the proposed switching mechanism, but the Discussion says its physiological relevance remains uncertain; the paper does not establish that it explains an acute response to changing metabolic states. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHNF-4α and COUP-TF compete for a mutual binding site and create a functional antagonism, respectively actively recruiting or blocking the transcriptional machinery, which is essential for expression of SHBG in the liver.
“Competing for a mutual binding site, HNF-4α and COUP-TF create a functional antagonism, respectively, actively recruiting or blocking the transcriptional machinery, which is essential for expression of SHBG in the liver.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [85]
The Discussion says HNF-4 and COUP-TF bind the same FP1 sequence, and the trans-activation experiments show that COUP-TF represses HNF-4-induced SHBG promoter activity in HepG2 cells. But the Discussion presents their interactions with transcriptional machinery as possible mechanisms, says their physiological relevance remains to be seen, and does not establish that this antagonism is essential for SHBG expression in the liver. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFurther characterization of this upstream region identified binding sites for COUP-TF and HNF-4α.
“Further characterization of this upstream region identified binding sites for chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and hepatocyte nuclear factor-4 alpha (HNF-4α) [85].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [85]
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Cites
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Functional Association between CBP and HNF4 inTrans-activation
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DIETARY LIPIDS : AN ADDITIONAL REGULATOR OF PLASMA LEVELS OF SEX HORMONE BINDING GLOBULIN
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Research works printed but not linked: 4
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Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action
Hammond, G. L. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0070 · Cited by 356 · see citing works
Self-citationNovel insights in SHBG regulation and clinical implications
Simó, R., Sáez-López, C., Barbosa-Desongles, A., Hernández, C., & Selva, D. M. (2015) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2015.05.001 · Cited by 335 · see citing works
Diverse Roles for Sex Hormone-Binding Globulin in Reproduction
Hammond, G. L. (2011) · Biology of Reproduction · doi:10.1095/biolreprod.111.092593 · Cited by 317 · see citing works
Self-citationCoviello, A. D., Haring, R., Wellons, M., Vaidya, D., Lehtimäki, T., Keildson, S., Lunetta, K. L., He, C., Fornage, M., Lagou, V., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002805 · Cited by 250 · see citing works
Evolving utility of sex hormone-binding globulin measurements in clinical medicine
Hammond, G. L., Wu, T.-S., & Simard, M. (2012) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e328353732f · Cited by 104 · see citing works
Self-citationNarinx, N., David, K., Walravens, J., Vermeersch, P., Claessens, F., Fiers, T., Lapauw, B., Antonio, L., & Vanderschueren, D. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04562-1 · Cited by 96 · see citing works
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Azrad, M., Gower, B. A., Hunter, G. R., & Nagy, T. R. (2012) · Obesity · doi:10.1038/oby.2011.375 · Cited by 33 · see citing works
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Self-citation
- Authors
- Jänne, M., & Hammond, G. L.
- Affiliations
- Western University (CA)
- Corresponding author
- Hammond, Geoffrey L.
- ORCID
- Hammond, Geoffrey L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1998-12
- Volume
- 273
- Issue
- 51
- Pages
- 34105-34114
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2037284300
- Cited by
- 94
- References
- 3
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 1 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 7 · 2016: 3 · 2015: 2 · 2014: 3 · 2013: 1 · 2012: 8
- FWCI
- 0.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- sex hormone-binding globulin, TATA-less promoter, HNF4, COUP-TF, transcriptional regulation, TATA-binding protein, TFIID, transcriptional repression, transcriptional activation, hepatocytes, DNase I footprinting, preinitiation complex
- MeSH terms
- Animals, Base Sequence, Deoxyribonuclease I, DNA-Binding Proteins, Gene Expression Regulation, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Luciferases, Molecular Sequence Data, Phosphoproteins, Promoter Regions, Genetic, Recombinant Fusion Proteins, Sequence Homology, Nucleic Acid, Sex Hormone-Binding Globulin, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, Mutagenesis, Site-Directed, TATA Box, Sequence Alignment, Cardiopulmonary Resuscitation, Sequence Deletion, Genes, Reporter, DNA Footprinting, Rats, Hepatocyte Nuclear Factor 4, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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