Scientists identify a gene capable of repairing congenital heart defects

Neural crest cell with enlarged embryonic heart. Credit: Mani Laboratory

A genetic disorder of PRDM6 causes persistence of the arterial duct (PDA), a common congenital heart defect in premature infants, suggesting a potential target for the 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, bones and cartilage of the face and especially 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 Overview.

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 in the Department of Medicine and Genetics discovered that the PRDM6 gene regulates neural crest cell (NCC) differentiation and migration.

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 whether a decrease in PRDM6 was associated with impaired cardiac NCC 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 demonstrated that a decrease in the expression of PRDM6 altered their migration and their 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 abnormality. 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 meeting a need. unsatisfied – restore the function of damaged heart tissue. for millions of patients with cardiovascular disease.

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


Understanding congenital heart defects, one chicken at a time


More information:
Lingjuan Hong et al, Prdm6 controls heart development by regulating neural crest cell differentiation and migration, JCI Overview (2022). DOI: 10.1172/jci.insight.156046

Provided by Yale University

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