The molecular functions of hepatocyte nuclear factors – In and beyond the liver
Abstract
The hepatocyte nuclear factors (HNFs) namely HNF1α/β, FOXA1/2/3, HNF4α/γ and ONECUT1/2 are expressed in a variety of tissues and organs, including the liver, pancreas and kidney. The spatial and temporal manner of HNF expression regulates embryonic development and subsequently the development of multiple tissues during adulthood. Though the HNFs were initially identified individually based on their roles in the liver, numerous studies have now revealed that the HNFs cross-regulate one another and exhibit synergistic relationships in the regulation of tissue development and function. The complex HNF transcriptional regulatory networks have largely been elucidated in rodent models, but less so in human biological systems. Several heterozygous mutations in these HNFs were found to cause diseases in humans but not in rodents, suggesting clear species-specific differences in mutational mechanisms that remain to be uncovered. In this review, we compare and contrast the expression patterns of the HNFs, the HNF cross-regulatory networks and how these liver-enriched transcription factors serve multiple functions in the liver and beyond, extending our focus to the pancreas and kidney. We also summarise the insights gained from both human and rodent studies of mutations in several HNFs that are known to lead to different disease conditions.
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General hepatocyte-specific eRegulons were found for CEBPA, HNF1A, HNF4A, ONECUT1, FOXA1 and NFIB, and zonation-associated eRegulons such as ESR1 and SOX9 periportally and PPARG and AR pericentrally.
“We found general hepatocyte-specific eRegulons for CEBPA, HNF1A, HNF4A, ONECUT1, FOXA1 and NFIB21–23, and zonation-associated eRegulons such as ESR1 and SOX9 periportally24,25 and PPARG and AR pericentrally26,27.”
From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [22]
HNF4A controls genes that are crucial for liver functions, primarily through binding to enhancers.
“Hepatocyte nuclear factor 4A (HNF4A/NR2a1), a transcriptional regulator of hepatocyte identity, controls genes that are crucial for liver functions, primarily through binding to enhancers.”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [3]
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HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements
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Enhancer grammar of liver cell types and hepatocyte zonation states
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- Authors
- Lau, H. H., Ng, N. H. J., Loo, L. S. W., Jasmen, J. B., & Teo, A. K. K.
- Affiliations
- Institute of Molecular and Cell Biology (SG)
- Nanyang Technological University (SG)
- National University of Singapore (SG)
- Corresponding author
- Teo, Adrian Kee Keong
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 68
- Issue
- 5
- Pages
- 1033-1048
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2768491523
- Cited by
- 250
- References
- 5
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 29 · 2023: 23 · 2022: 42 · 2021: 50 · 2020: 46 · 2019: 16 · 2018: 4
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- Funders
- AGA
- IMCB
- 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
- hepatocyte nuclear factor, HNF1A, HNF1B, FOXA1, FOXA2, FOXA3, HNF4α, Onecut1, ONECUT2, transcriptional regulatory networks, histogenesis, pancreas, kidney, liver, heterozygous mutation
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Humans, Kidney, Liver, Mutation, Pancreas, Tissue Distribution, Gene Expression Regulation, Developmental, Hepatocyte Nuclear Factors, Gene Regulatory Networks, Metabolic Networks and Pathways
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