Researchers at Gladstone Institutes have identified genetic mechanisms involved in heart defects that develop in some fetuses born to diabetic women. They discovered these mechanisms at work in a subset of cells that become part of the developing aorta and pulmonary artery, which have unusually elevated retinoic acid activity causing them to behave like other types of heart cells. Details are published in Nature Cardiovascular Research in a paper titled, “Single-cell multimodal analyses reveal epigenomic and transcriptomic basis for birth defects in maternal diabetes.” 

Babies born to women with diabetes are five times more likely to have a congenital heart defect. “There are a number of environmental factors, including maternal diabetes, that we know are associated with birth defects,” said Deepak Srivastava, MD, Gladstone president and senior author of the study. In fact, maternal type I or type II diabetes is one of the most common non-genetic causes of congenital heart defects before conception. These forms are distinct from gestational diabetes, which develops later in pregnancy. However the mechanisms that lead to the development of these defects have remained a mystery making it difficult to prevent the damage from occurring. “This kind of modern, single-cell study can reveal these mechanisms and, ultimately, help us design therapeutic interventions to lower the risk of birth defects,” Srivastava said. 

The scientists used a model of diabetic mice with high rates of heart defects in their offspring for the study. They collected more than 30,000 different cells from the developing hearts of embryos growing in the diabetic mice and then analyzed the three-dimensional configuration of DNA as well as the levels of different mRNA molecules in each individual cell. By looking at both kinds of data, the team could assess differences between normal and fetal cells exposed to maternal diabetes and the genetic pathways involved in regulating observed changes. 

Their data revealed more than 4,000 differences in the DNA from normal mice fetuses and those exposed to maternal diabetes. In total, 97% of the differences were in two small subsets of cells: one group is responsible for forming a critical section of the heart separating the aorta and pulmonary artery and chambers of the heart, and the second group is involved in craniofacial development. The subpopulation of heart cells had elevated levels of ALX3 activity, a gene involved in regulating cell growth, division, and movement during development. “This subset of cells was never previously recognized as being different [from] the cells around it, so it was quite surprising to discover that those cells were so selectively vulnerable to maternal diabetes and responsible for the defects observed,” Srivastava noted.

Additionally, this subset of heart cells had high levels of retinoic acid, which is known to cause birth defects such as hydrocephalus, cleft palate, as well as learning and intellectual disabilities. In normal development, higher levels of retinoic acid are typically found only in cells in the posterior part of the forming heart. Because the cells higher up in the aorta and pulmonary arteries had similar levels of retinoic acid, they were being induced to act more like posterior heart cells. And this likely caused the observed defects in the fetuses from diabetic mothers. 

While this study is a good first step, there is more work to be done to fill the gaps. For example, it is not clear exactly how maternal diabetes changes levels of retinoic acid, and why this subset of heart cells is particularly susceptible to that increase. 

Furthermore, the scientists believe that they now have a template for using single-cell-based studies to link environmental factors and birth defects more broadly. Similar experiments to those used here could be used to investigate defects in other organ systems as well as fetal defects caused by exposure to drugs during gestation. Ultimately, “the goal is eventually to have therapeutics that we can offer to mothers that lower their risk of all these birth defects,” Srivastava said.

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