Yale scientists identify a gene capable of repairing congenital heart defects

A genetic disease in PRDM6 causes persistent ductus arteriosus (PDA), a common congenital heart defect in premature infants – suggesting a potential target for treatment of congenital heart disease.

Each year, 3,000 newborns in the United States are diagnosed with PDA. Infants born prematurely are at higher risk for PDA. The ductus arteriosus – a temporary blood vessel that connects the aorta and the pulmonary artery – allows blood to flow directly from the heart to the aorta during embryonic development. The vessel normally closes after birth when smooth muscle cells contract.

“The disease is caused by a defect in a region of the brain called the neural crest. This part of the brain appears transiently and is important because cells in this region behave like stem cells and contribute to the skull, facial bones and cartilage, and most importantly, the heart,” said Arya Mani, MD, lead author of the study and professor of medicine and genetics at the Yale School of Medicine.

The study appears in the journal JCI Insight.

The Mani lab at the Yale Cardiovascular Research Center analyzed gene expression data in mice. The research team focused on PRDM6, an epigenetic modifier that regulates gene expression. Using RNA sequencing, Mani and his colleagues from the Department of Medicine and Genetics discovered that PRDM6 This gene regulates the differentiation and migration of neural crest cells (NCC).

Cardiac NCCs (CNCCs) are essential for the cardiovascular development of an embryo. These multipotent migratory cells are part of a network that produces melanocytes, neurons, cartilage and connective tissue in humans.

To test if diminished PRDM6 was associated with impaired NCC cardiac differentiation, the authors used an in vivo imaging technique called fate mapping. Smooth muscle cells and NCCs were labeled with a colored dye and monitored throughout development. This allowed the research team to study the cellular behavior and genetic characteristics of developing embryos. The technique has demonstrated that a decrease PRDM6 expression impaired their migration and differentiation into smooth muscle cells. Using single-cell RNA sequencing, they were able to show that upregulation of the CNCC specification gene, Wnt1 is the cause of the cardiac anomaly. The increased levels resulted in altered migration, which could be reversed by inhibiting Wnt1.

The authors suggest that their findings can be applied to other patients with congenital heart disease caused by epigenetic dysregulation, such as those caused by alcohol or folic acid deficiency during pregnancy and could bring scientists closer to addressing an unmet need. satisfied – restore the function of damaged heart tissue. for millions of patients with cardiovascular disease.

“We were able to better understand how the environment, such as drug toxicity or lack of vitamins, can cause disease. In a sense, we gain insight not only into how disease arises when PRDM6 is deficient, but also of the number of congenital heart diseases that occur and can be prevented or cured either by manipulating Wnt1, or by supplementing the nutrients and vitamins that mothers need and avoiding alcohol or drugs that can alter epigenetic regulation,” said said Mani.

Other authors include Lingjuan Hong, Na Li, Victor Gasque, Sameet Mehta, Lupeng Ye, Yinyu Wu, Jinyu Li, Anne Eichmann, Caroline Hendry, David van Dijk, Karen Hirschi, Hong-Jae Park and Jürgen Ruland.