Maternal diabetes is a common risk factor for congenital heart defects (CHDs) in infants, suggesting hyperglycemia disrupts specific morphogenesis events in the embryonic heart. DNA methylation plays important roles in embryonic development. Our previous study demonstrated that global DNA methylation is significantly increased in early stage embryos from diabetic pregnancy compared to that from nondiabetic pregnancy. Isl1 marks the second heart field cardiac progenitor population, which contribute to outflow tract, right ventricle, and much of the atria. We hypothesize that conditional knockout of Dnmt3a and Dnmt3b will ameliorate maternal diabetes-induced CHDs derived from the defects of the second heart field. We used the well-established type 1 diabetic embryopathy mouse model, in which diabetes was induced by streptozotocin for our in vivo studies. To determine if conditional deletion of Dnmt3a and/or Dnmt3b in the second heart field progenitors ameliorates specific CHDs in diabetic pregnancy, we induced diabetic embryopathy in Dnmt3af/f/3bf/f female mice, which bred with Dnmt3af/w/Dnmt3bf/w;Isl1-Cre male mice, embryos were harvested at embryonic day 12.5 (E12.5) to determine DNA methylation activity and at E17.5 for the presence of CHDs. Embryos of diabetic dams had a 50% CHDs, double deletion of Dnmt3a and Dnmt3b significantly ameliorated CHDs derived from the defect of the second heart field from 27% to 0%, while dramatically enhanced CHD derived from the first heart field incidence 23% to 50%, mainly Hypoplastic left heart syndrome (HLHS). Our study demonstrates that DNA methylation plays an important role in the regulation of diabetic pregnancies. CHD of SHF are rescued by dKO of Dnmt3a/3b, while CHD of SHF enhanced. This suggests that targeting of DNA methylation may be a viable strategy for suppression of congenital heart defects in fetuses of diabetic pregnancies.


F. Ye: None. P. Yang: None.


National Institutes of Health (1R01134368)

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