One faulty gene copy can make the heart’s DNA fold the wrong way

Congenital heart disease is the most common birth defect, affecting roughly one in every 100 newborns. This condition, which can stem from various causes, has long puzzled researchers. However, a recent study by scientists at the Gladstone Institutes suggests a novel explanation: a single faulty copy of the TBX5 gene can disrupt the folding of DNA within heart cells, leading to severe developmental issues.

TBX5 is a gene crucial for heart development, playing a role beyond just controlling gene activity. It helps organize DNA into a three-dimensional structure essential for proper heart cell function. According to Dr. Benoit Bruneau, director of the Gladstone Institute of Cardiovascular Disease, losing just one copy of TBX5 can have a significant impact on heart development, even when the second copy is functional.

To understand this phenomenon, the researchers employed advanced computational models to analyze data from thousands of individual cells. This approach revealed that losing one copy of TB5 affects the physical folding of DNA, disrupting the organization of genetic material at multiple levels, including compartments, domains, and chromatin loops. Each of these structures plays a role in making specific genetic instructions accessible to heart cells.

The study, published in Science, demonstrated that TBX5 functions like a GPS for a molecular motor called cohesin, guiding it to the right locations on DNA to form chromatin loops. These loops enable distant genetic switches, known as enhancers, to interact with specific genes, activating the necessary instructions for heart cell development. When TBX5 levels are insufficient, these loops fail to form properly, leading to incorrect folding of DNA and the failure of critical heart development genes to activate.

Interestingly, the researchers found that the impact of TBX5 loss varies among different types of heart cells and individual cells. This variation may explain why individuals with the same genetic mutation can exhibit different heart defects. While the study provides new insights into congenital heart disease, the researchers believe the same mechanism could be involved in other developmental disorders.