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Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease
Madhumita Basu, … , Zhe Han, Vidu Garg
Madhumita Basu, … , Zhe Han, Vidu Garg
Published October 19, 2017
Citation Information: JCI Insight. 2017;2(20):e95085. https://doi.org/10.1172/jci.insight.95085.
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Research Article Cardiology Genetics

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

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Abstract

Birth defects are the leading cause of infant mortality, and they are caused by a combination of genetic and environmental factors. Environmental risk factors may contribute to birth defects in genetically susceptible infants by altering critical molecular pathways during embryogenesis, but experimental evidence for gene-environment interactions is limited. Fetal hyperglycemia associated with maternal diabetes results in a 5-fold increased risk of congenital heart disease (CHD), but the molecular basis for this correlation is unknown. Here, we show that the effects of maternal hyperglycemia on cardiac development are sensitized by haploinsufficiency of Notch1, a key transcriptional regulator known to cause CHD. Using ATAC-seq, we found that hyperglycemia decreased chromatin accessibility at the endothelial NO synthase (Nos3) locus, resulting in reduced NO synthesis. Transcription of Jarid2, a regulator of histone methyltransferase complexes, was increased in response to reduced NO, and this upregulation directly resulted in inhibition of Notch1 expression to levels below a threshold necessary for normal heart development. We extended these findings using a Drosophila maternal diabetic model that revealed the evolutionary conservation of this interaction and the Jarid2-mediated mechanism. These findings identify a gene-environment interaction between maternal hyperglycemia and Notch signaling and support a model in which environmental factors cause birth defects in genetically susceptible infants.

Authors

Madhumita Basu, Jun-Yi Zhu, Stephanie LaHaye, Uddalak Majumdar, Kai Jiao, Zhe Han, Vidu Garg

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Figure 1

Hyperglycemia downregulates Notch1 pathway.

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Hyperglycemia downregulates Notch1 pathway.
(A) Transcript levels of Not...
(A) Transcript levels of Notch1, Hey1, Hey2, EfnB2, and Nrg1 in AVM cells cultured in HG (25 mM) for 24 hours (blue) and 48 hours (red) by RT-qPCR (n ≥ 3). Comparisons to NG (5.5 mM), represented by the dotted line set to 1; data represent mean ± SEM. (B) N1ICD and HEY2 protein expression in AVM cells cultured in NG and HG for 24 hours and 48 hours. (C) Quantification of protein expression normalized to GAPDH (n = 3; mean ± SEM). (D) Examination of E13.5 WT murine hearts of nondiabetic and diabetic dams shows downregulation of Notch1, Hey2, EfnB2, Nrg1, and Bmp10 mRNA by RT-qPCR (n = 6 pooled hearts/group; mean ± SD). (E–H) Decreased expression of N1ICD and HEY2 in embryonic hearts exposed to maternal diabetes by immunohistochemistry (n = 3). Square boxes in left column in E–H are shown in higher magnifications from left to right. LV, left ventricle; RV, right ventricle; IVS, interventricular septum. *P < 0.05, 2-tailed Student’s t test in C, with Holm-Bonferroni correction in A and D. Scale bars: 100 μm (E–H, left column); 20 μm (E–H, center and right columns).

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