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Complications

Increased DNA Methyltransferase 3b (Dnmt3b)-Mediated CpG Island Methylation Stimulated by Oxidative Stress Inhibits Expression of a Gene Required for Neural Tube and Neural Crest Development in Diabetic Pregnancy

  1. Dan Wei and
  2. Mary R. Loeken⇑
  1. Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, MA
  1. Corresponding author: Mary R. Loeken, mary.loeken{at}joslin.harvard.edu.
Diabetes 2014 Oct; 63(10): 3512-3522. https://doi.org/10.2337/db14-0231
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Abstract

Previous studies have shown that diabetic embryopathy results from impaired expression of genes that are required for formation of embryonic structures. We have focused on Pax3, a gene that is expressed in embryonic neuroepithelium and is required for neural tube closure. Pax3 expression is inhibited in embryos of diabetic mice due to hyperglycemia-induced oxidative stress. DNA methylation silences developmentally expressed genes before differentiation. We hypothesized that hypomethylation of Pax3 upon neuroepithelial differentiation may be inhibited by hyperglycemia-induced oxidative stress. We tested this using embryos of pregnant hyperglycemic mice and mouse embryonic stem cells (ESC). Methylation of a Pax3 CpG island decreased upon neurulation of embryos and formation of neuronal precursors from ESC. In ESC, this was inhibited by oxidative stress. Use of short hairpin RNA in ESC demonstrated that DNA methyltransferase 3b (Dnmt3b) was responsible for methylation and silencing of Pax3 before differentiation and by oxidative stress. Although expression of Dnmt3b was not affected by oxidative stress, DNA methyltransferase activity was increased. These results indicate that hyperglycemia-induced oxidative stress stimulates Dnmt3b activity, thereby inhibiting chromatin modifications necessary for induction of Pax3 expression during neurulation and thus providing a molecular mechanism for defects caused by Pax3 insufficiency in diabetic pregnancy.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0231/-/DC1.

  • The content of this article is solely the responsibility of M.R.L. and does not necessarily represent the official views of the National Institutes of Health.

  • Received February 10, 2014.
  • Accepted May 10, 2014.
  • © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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Increased DNA Methyltransferase 3b (Dnmt3b)-Mediated CpG Island Methylation Stimulated by Oxidative Stress Inhibits Expression of a Gene Required for Neural Tube and Neural Crest Development in Diabetic Pregnancy
Dan Wei, Mary R. Loeken
Diabetes Oct 2014, 63 (10) 3512-3522; DOI: 10.2337/db14-0231

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Increased DNA Methyltransferase 3b (Dnmt3b)-Mediated CpG Island Methylation Stimulated by Oxidative Stress Inhibits Expression of a Gene Required for Neural Tube and Neural Crest Development in Diabetic Pregnancy
Dan Wei, Mary R. Loeken
Diabetes Oct 2014, 63 (10) 3512-3522; DOI: 10.2337/db14-0231
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