The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Insulin Gene Expression Is Regulated by DNA Methylation
Open accessAbstract
BACKGROUND: Insulin is a critical component of metabolic control, and as such, insulin gene expression has been the focus of extensive study. DNA sequences that regulate transcription of the insulin gene and the majority of regulatory factors have already been identified. However, only recently have other components of insulin gene expression been investigated, and in this study we examine the role of DNA methylation in the regulation of mouse and human insulin gene expression. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA samples from several tissues were bisulfite-treated and sequenced which revealed that cytosine-guanosine dinucleotide (CpG) sites in both the mouse Ins2 and human INS promoters are uniquely demethylated in insulin-producing pancreatic beta cells. Methylation of these CpG sites suppressed insulin promoter-driven reporter gene activity by almost 90% and specific methylation of the CpG site in the cAMP responsive element (CRE) in the promoter alone suppressed insulin promoter activity by 50%. Methylation did not directly inhibit factor binding to the CRE in vitro, but inhibited ATF2 and CREB binding in vivo and conversely increased the binding of methyl CpG binding protein 2 (MeCP2). Examination of the Ins2 gene in mouse embryonic stem cell cultures revealed that it is fully methylated and becomes demethylated as the cells differentiate into insulin-expressing cells in vitro. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that insulin promoter CpG demethylation may play a crucial role in beta cell maturation and tissue-specific insulin gene expression.
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Cites
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“Forskolin increases intracellular cAMP levels in the beta cell and activates kinases that phosphorylate CRE binding proteins which stimulate CRE-dependent transcription [25].”
BackgroundEpigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?
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DNA Methylation-Related Chromatin Remodeling in Activity-Dependent Bdnf Gene Regulation
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Cited by
The alternative role of DNA methylation in splicing regulation
Lev Maor, G., Yearim, A., & Ast, G. (2015) · Trends in Genetics · doi:10.1016/j.tig.2015.03.002 · Cited by 567
Talens, R. P., Christensen, K., Putter, H., Willemsen, G., Christiansen, L., Kremer, D., Suchiman, H. E. D., Slagboom, P. E., Boomsma, D. I., & Heijmans, B. T. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00835.x · Cited by 300
Yang, B. T., Dayeh, T. A., Kirkpatrick, C. L., Taneera, J., Kumar, R., Groop, L., Wollheim, C. B., Nitert, M. D., & Ling, C. (2011) · Diabetologia · doi:10.1007/s00125-010-1967-6 · Cited by 251
DNA methylation in metabolic disorders
Barres, R., & Zierath, J. R. (2011) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.110.001933 · Cited by 174
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Metadata
- Authors
- Kuroda, A., Rauch, T. A., Todorov, I., Ku, H. T., Al-Abdullah, I. H., Kandeel, F., Mullen, Y., Pfeifer, G. P., & Ferreri, K.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-09-09
- Volume
- 4
- Issue
- 9
- Pages
- e6953
- ISSN
- 1932-6203 (ISSN-L)
- OpenAlex
- W1963929665
- Cited by
- 311
- References
- 49
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Open access
- gold
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