FOXA1 potentiates lineage-specific enhancer activation through modulating TET1 expression and function
Open accessAbstract
Forkhead box A1 (FOXA1) is an FKHD family protein that plays pioneering roles in lineage-specific enhancer activation and gene transcription. Through genome-wide location analyses, here we show that FOXA1 expression and occupancy are, in turn, required for the maintenance of these epigenetic signatures, namely DNA hypomethylation and histone 3 lysine 4 methylation. Mechanistically, this involves TET1, a 5-methylcytosine dioxygenase. We found that FOXA1 induces TET1 expression via direct binding to its cis-regulatory elements. Further, FOXA1 physically interacts with the TET1 protein through its CXXC domain. TET1 thus co-occupies FOXA1-dependent enhancers and mediates local DNA demethylation and concomitant histone 3 lysine 4 methylation, further potentiating FOXA1 recruitment. Consequently, FOXA1 binding events are markedly reduced following TET1 depletion. Together, our results suggest that FOXA1 is not only able to recognize but also remodel the epigenetic signatures at lineage-specific enhancers, which is mediated, at least in part, by a feed-forward regulatory loop between FOXA1 and TET1.
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A previous study observed a similar effect at FOXA1 bound enhancers in LNCaP prostate cancer cells in which knockdown of FOXA1 reduced 5hmC without gain of 5mC.
“A previous study observed a similar effect at FOXA1 bound enhancers in LNCaP prostate cancer cells in which knockdown of FOXA1 reduced 5hmC without gain of 5mC (24).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [24]
In Results (‘FOXA1 expression contributes to lineage-specific enhancer activation’), FOXA1 knockdown in LNCaP cells significantly decreased 5hmC at FOXA1-binding sites, while average 5mC intensity was not substantially affected. The same passage reports moderate 5mC increases at individual sites by MeDIP-PCR (Supplementary Figure S3), so ‘without gain of 5mC’ is supported at the genome-wide level but not without qualification. (LLM, conf=0.89)
Experimental — accuracy not yet measuredRecent reports have identified TFs that interact with TET proteins to maintain low 5mC and high 5hmC at enhancers.
“Recent reports have identified TFs that interact with TET proteins to maintain low 5mC and high 5hmC at enhancers (23, 24).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [24]
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Cites
Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
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Cited by
Sorted by citations
Thakur, A., Wong, J. C. H., Wang, E. Y., Lotto, J., Kim, D., Cheng, J., Mingay, M., Cullum, R., Moudgil, V., Ahmed, N., et al. (2019) · Hepatology · doi:10.1002/hep.30631 · Cited by 75 · see citing works
Decoding the role of TET family dioxygenases in lineage specification
Wu, X., Li, G., & Xie, R. (2018) · Epigenetics & Chromatin · doi:10.1186/s13072-018-0228-7 · Cited by 43 · see citing works
- Authors
- Yang, Y. A., Zhao, J. C., Fong, K.-W., Kim, J., Li, S., Song, C., Song, B., Zheng, B., He, C., & Yu, J.
- Affiliations
- Northwestern University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Yu, Jindan
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-06-01
- Volume
- 44
- Issue
- 17
- Pages
- 8153-8164
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC5041455
- OpenAlex
- W2418751876
- Cited by
- 69
- References
- 1
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 4 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 13 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 1
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- U.S. Department of Defense (W81XWH, W81XWH-13)
- Howard Hughes Medical Institute
- National Institutes of Health (W81XWH)
- National Human Genome Research Institute (R01HG006827)
- National Cancer Institute (R01CA172384, T32 CA09560, CA09560, T32CA080621, P30CA060553, T32CA009560)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- FOXA1, TET1, enhancer activation, DNA demethylation, histone H3 lysine 4 methylation, CXXC domain, epigenetic regulation, transcriptional regulation
- MeSH terms
- Enhancer Elements, Genetic, Humans, Mixed Function Oxygenases, Models, Biological, Protein Binding, Proto-Oncogene Proteins, Transcription, Genetic, Cell Lineage, Epigenesis, Genetic, Cell Line, Tumor, Hepatocyte Nuclear Factor 3-alpha, HEK293 Cells
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