Cited by 122Epigenetics and DNA MethylationPluripotent Stem Cells ResearchGenomics and Chromatin Dynamics

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Paradoxical Role of DNA Methylation in Activation of FoxA2 Gene Expression during Endoderm Development

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Bahar Halpern, Keren, Vana, Tal, Walker, Michael D.·2014·Journal of Biological Chemistry

DOI 10.1074/jbc.m114.573469PMC PMC4156079

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Abstract

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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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)
DOI: 10.1074/jbc.m114.573469
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 2261 d)
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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Paradoxical Role of DNA Methylation in Activation of FoxA2 Gene Expression during Endoderm Development

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