HNF4A and HNF1A exhibit tissue specific target gene regulation in pancreatic beta cells and hepatocytes
Open accessAbstract
HNF4A and HNF1A encode transcription factors that are important for the development and function of the pancreas and liver. Mutations in both genes have been directly linked to Maturity Onset Diabetes of the Young (MODY) and type 2 diabetes (T2D) risk. To better define the pleiotropic gene regulatory roles of HNF4A and HNF1A, we generated a comprehensive genome-wide map of their binding targets in pancreatic and hepatic cells using ChIP-Seq. HNF4A was found to bind and regulate known (ACY3, HAAO, HNF1A, MAP3K11) and previously unidentified (ABCD3, CDKN2AIP, USH1C, VIL1) loci in a tissue-dependent manner. Functional follow-up highlighted a potential role for HAAO and USH1C as regulators of beta cell function. Unlike the loss-of-function HNF4A/MODY1 variant I271fs, the T2D-associated HNF4A variant (rs1800961) was found to activate AKAP1, GAD2 and HOPX gene expression, potentially due to changes in DNA-binding affinity. We also found HNF1A to bind to and regulate GPR39 expression in beta cells. Overall, our studies provide a rich resource for uncovering downstream molecular targets of HNF4A and HNF1A that may contribute to beta cell or hepatic cell (dys)function, and set up a framework for gene discovery and functional validation.
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Expression of HNF1A, HNF4A, and FOXA2 typically peaks during the early progenitor stage and decreases toward the final hepatocyte-like cell stage.
“This finding is consistent with other reports that these genes’ expression typically peaks during early progenitor stage and decreases towards the final hepatocyte-like cells stage24–26.”
From Temporal proteomic profiling of iPSC-derived human liver organoids reveals optimal maturation for drug metabolism and toxicology (2026) · cites this paper as [24]
The Results section on genome-wide targets states that HNF4A expression peaks during the early progenitor stage and decreases by the hepatocyte-like cell stage. The passages found do not establish the same expression pattern for HNF1A or FOXA2. Page numbers are not available in our copy. (LLM, conf=0.88)
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- Authors
- Ng, 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., & Teo, A. K. K.
- Affiliations
- Agency for Science, Technology and Research (SG)
- National University of Singapore (SG)
- Corresponding author
- Teo, Adrian Kee Keong
- ORCID
- Venue
- Nature Communications
- Published
- 2024-06-22
- Volume
- 15
- Issue
- 1
- Pages
- 4288-4288
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11193738
- OpenAlex
- W4399917919
- Cited by
- 57
- References
- 90
- Citations by year
- 2026: 31 · 2025: 23 · 2024: 3
- FWCI
- 24.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Greater South Information System
- Funders
- A*STAR | Institute of Molecular and Cell Biology
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- HNF4α, HNF1A, transcription factor binding sites, tissue-specific gene regulation, pancreatic beta cells, hepatocytes, maturity-onset diabetes of the young, type 2 diabetes, USH1C, AKAP1, GAD-2, HOPX, ABCD3, MAP3K11, DNA binding affinity
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Gene Expression Regulation, Humans, Organ Specificity, Hepatocytes, Insulin-Secreting Cells, Mice, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 4, A Kinase Anchor Proteins
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