Half a TBX5 gene copy disrupts heart DNA folding, linking to birth defects

Scientists at Gladstone Institutes reported that reducing TBX5 dosage by half triggers a complete collapse of the three-dimensional genome architecture in human heart cells. They differentiated stem cells into cardiomyocytes with normal, one-copy-lost, and two-copy-lost TBX5, then applied high-resolution 3D mapping and custom computational analyses to millions of data points. The loss of a single TBX5 allele disrupted DNA folding at every hierarchical level—large compartments, smaller domains and chromatin loops—leading to widespread changes in gene expression.

Distinct patterns emerged between atrial and ventricular cells and among individual cells, offering a possible explanation for why identical mutations produce varied heart defects. Published in Science, the study suggests that misfolding of the genome’s instruction manual may be a common mechanism behind many birth defects. Future investigations will pinpoint when TBX5 begins shaping the genome and assess whether other disease-associated proteins act in a similar fashion.