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

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

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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Crossref · 10.1074/jbc.m114.573469

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Authors
Bahar Halpern, K., Vana, T., & Walker, M. D.
Affiliations
Weizmann Institute of Science (IL)
Corresponding author
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)
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
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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