The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index.
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 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]
In the citing paper
“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]
In the citing paper
“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]
Citations
Cites
Jaenisch, R., & Bird, A. (2003) · Nature Genetics · doi:10.1038/ng1089 · Cited by 6,325
Cancer-epigenetics comes of age
Jones, P. A., & Laird, P. W. (1999) · Nature Genetics · doi:10.1038/5947 · Cited by 2,358
The Polycomb group protein EZH2 directly controls DNA methylation
Viré, E., Brenner, C., Deplus, R., Blanchon, L., Fraga, M., Didelot, C., Morey, L., Van Eynde, A., Bernard, D., Vanderwinden, J.-M., et al. (2006) · Nature · doi:10.1038/nature04431 · Cited by 2,204
Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1393 · Cited by 1,843 · cited 1×
“Oct4 expression was down-regulated by 40% (29), whereas CXCR4 and SOX17 were up-regulated (5and 4,000-fold, respectively) following exposure to differentiation conditions for 3 days (18), in the absence or in the presence of 5-aza-dC (Fig.”
BackgroundEfficient differentiation of human embryonic stem cells to definitive endoderm
D'Amour, K. A., Agulnick, A. D., Eliazer, S., Kelly, O. G., Kroon, E., & Baetge, E. E. (2005) · Nature Biotechnology · doi:10.1038/nbt1163 · Cited by 1,730
Pioneer transcription factors: establishing competence for gene expression
Zaret, K. S., & Carroll, J. S. (2011) · Genes & Development · doi:10.1101/gad.176826.111 · Cited by 1,589
Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitionsPreprint
Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H., & Helin, K. (2006) · Genes & Development · doi:10.1101/gad.381706 · Cited by 1,286
Miyazaki, J., Araki, K., Yamato, E., Ikegami, H., Asano, T., Shibasaki, Y., Oka, Y., & Yamamura, K. (1990) · Endocrinology · doi:10.1210/endo-127-1-126 · Cited by 1,267
CpG islands as gene markers in the human genome
Larsen, F., Gundersen, G., Lopez, R., & Prydz, H. (1992) · Genomics · doi:10.1016/0888-7543(92)90024-m · Cited by 922
Transposable elements have rewired the core regulatory network of human embryonic stem cells
Kunarso, G., Chia, N., Jeyakani, J., Hwang, C., Lu, X., Chan, Y.-S., Ng, H., & Bourque, G. (2010) · Nature Genetics · doi:10.1038/ng.600 · Cited by 777
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Ye, A. (2016) · Louisiana State University · doi:10.31390/gradschool_dissertations.2261
Gao, J. Q., Meng, C., Li, G. U. A. N., ZHANG, H., & Zhang, W. (2021) · Food Science and Technology · doi:10.1590/fst.44721
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Liu, P., Zhang, J., Du, D., Zhang, D., Jin, Z., Qiu, W., Zhou, X., Dong, S., Zhou, M., Zhao, H., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14752231
Liu, P., Zhang, J., Du, D., Zhang, D., Jin, Z., Qiu, W., Zhou, X., Dong, S., Zhou, M., Zhao, H., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14752228
Liu, P., Zhang, J., Du, D., Zhang, D., Jin, Z., Qiu, W., Zhou, X., Dong, S., Zhou, M., Zhao, H., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14752234
Habiburrahman, M., & Flanagan, J. M. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4951684
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Schardein, J. N., Moore, J., Olson, B., Kaufmann, S., Jimbo, M., Gross, K. X., Parks, S., Jenkins, T. G., Pastuszak, A. W., Hotaling, J. M., et al. (2025) · The Journal of Sexual Medicine · doi:10.1093/jsxmed/qdaf233
Mendoza, A. D., Nguyen, T. V., Ford, E., Poppe, D., Buckberry, S., Pflueger, J., Grimmer, M. R., Stolzenburg, S., Bogdanović, O., Oshlack, A., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20381823
Liu, P., Zhang, J., Du, D., Zhang, D., Jin, Z., Qiu, W., Zhou, X., Dong, S., Zhou, M., Zhao, H., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14752225
Mendoza, A. D., Nguyen, T. V., Ford, E., Poppe, D., Buckberry, S., Pflueger, J., Grimmer, M. R., Stolzenburg, S., Bogdanović, O., Oshlack, A., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20381817
Han, Y., Yang, J., Wang, H., Xu, Y., Wu, W., Chen, X., & Chen, Y. (2026) · Journal of International Medical Research · doi:10.1177/03000605261420924
Habiburrahman, M., & Flanagan, J. M. (2026) · Heliyon · doi:10.1016/j.heliyon.2026.e44652
Ramos‐Morales, E. (2021) · theses.fr (ABES) · doi:10.70675/c6b28473zf6b6z4024z99bfz05629f0484d7
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Metadata
- 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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