Paradoxical Role of DNA Methylation in Activation of FoxA2 Gene Expression during Endoderm Development
Open accessAbstract
The transcription factor FoxA2 is a master regulator of endoderm development and pancreatic beta cell gene expression. To elucidate the mechanisms underlying the activation of the FoxA2 gene during differentiation, we have compared the epigenetic status of undifferentiated human embryonic stem cells (hESCs), hESC-derived early endoderm stage cells (CXCR4+ cells), and pancreatic islet cells. Unexpectedly, a CpG island in the promoter region of the FoxA2 gene displayed paradoxically high levels of DNA methylation in expressing tissues (CXCR4+, islets) and low levels in nonexpressing tissues. This CpG island region was found to repress reporter gene expression and bind the Polycomb group protein SUZ12 and the DNA methyltransferase (DNMT)3b preferentially in undifferentiated hESCs as compared with CXCR4+ or islets cells. Consistent with this, activation of FoxA2 gene expression, but not CXCR4 or SOX17, was strongly inhibited by 5-aza-2'-deoxycytidine and by knockdown of DNMT3b. We hypothesize that in nonexpressing tissues, the lack of DNA methylation allows the binding of DNA methyltransferases and repressing proteins, such as Polycomb group proteins; upon differentiation, DNMT activation leads to CpG island methylation, causing loss of repressor protein binding. These results suggest a novel and unexpected role for DNA methylation in the activation of FoxA2 gene expression during differentiation.
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DNA methylation of a promoter or enhancer is correlated with increased transcription of a target gene.
“DNA methylation of a promoter or an enhancer has been shown to be correlated with increased transcription of a target gene47,49”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [47]
Single-gene studies have demonstrated that DNA methylation can activate gene expression.
“Single-gene studies have also demonstrated that DNA methylation can activate gene expression47–49.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [47]
RFX was previously shown to bind methylated DNA.
“this protein was previously shown to bind to methylated DNA47,51.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [47]
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- Authors
- Bahar Halpern, K., Vana, T., & Walker, M. D.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Walker, Michael D.
- ORCID
- Walker, Michael D.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 289
- Issue
- 34
- Pages
- 23882-23892
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4156079
- OpenAlex
- W2028313529
- Cited by
- 119
- References
- 47
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 12 · 2023: 10 · 2022: 10 · 2021: 13 · 2020: 11 · 2019: 11 · 2018: 11 · 2017: 8 · 2016: 12 · 2015: 4
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- FOXA2, DNA methylation, endoderm development, pancreatic beta cells, human embryonic stem cells, CpG islands, promoter methylation, DNMT3B, SUZ12, Polycomb group proteins, gene expression regulation, decitabine, SOX17, pancreatic islets
- MeSH terms
- Animals, Base Sequence, Cell Line, Endoderm, Flow Cytometry, Gene Expression Regulation, Humans, DNA Primers, DNA Methylation, Chromatin Immunoprecipitation, Mice, Hepatocyte Nuclear Factor 3-beta, Real-Time Polymerase Chain Reaction
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