Congenital heart disease is the most common birth defect, affecting about 1 in 100 babies born each year, according to ScienceDaily. One known cause involves TBX5, a gene that is important for building the heart and can be disrupted when a child inherits only one working copy instead of two.
Researchers at Gladstone Institutes now say TBX5 does more than regulate gene activity. In a study published in Science, the team found that the gene also helps organize DNA into the three-dimensional shape heart cells need to function properly.
The scientists used human stem cells that were turned into heart muscle cells and compared healthy cells with cells missing one or both copies of TBX5. With high-resolution DNA mapping and computer models, they found that losing even one copy could disrupt genome organization at multiple levels, including compartments, domains and chromatin loops.
According to the study, TBX5 helps guide a molecular motor called cohesin to the right spots on DNA, where it forms loops that connect genes with enhancers. When TBX5 levels drop, those loops form improperly and important heart-development genes may not turn on when needed.
The researchers also found differences between atrial and ventricular cells, as well as variation among cells of the same type, which could help explain why people with the same mutation can have different heart defects. The authors say the work offers a new way to think about haploinsufficiency and may point to a broader mechanism in other developmental disorders.
