A gene linked to congenital heart disease acts like an architect for the heart cell's DNA — and losing just one working copy can collapse the genome's carefully folded 3D structure, disrupting the genes needed to build a healthy heart. That's the finding from researchers at Gladstone Institutes, published in the journal Science.
Congenital heart disease is the most common birth defect, affecting about 1 in 100 babies. One culprit is TBX5, a gene that plays a critical role in building the heart. Some children have only one working copy instead of two. Why that single loss causes such severe problems — even though the second copy still works — has puzzled geneticists for years.
The team guided human stem cells into becoming heart muscle cells, deleted one or both copies of TBX5, and used high-resolution 3D mapping to examine DNA loops across thousands of individual cells. The result: TBX5 works like a GPS for a molecular motor called cohesin, helping it create chromatin loops that bring distant gene switches (enhancers) into contact with their target genes. When TBX5 drops to half its normal level, this organization collapses at every level — compartments, domains and loops — and crucial heart genes fail to switch on when needed.
Strikingly, individual heart cells did not all respond the same way. "This could help explain why people with the same mutation can have different heart defects," says first author Zoe Grant.
The team believes the mechanism may be far broader: "Many birth defects currently attributed to genetic mutations may actually be caused by the 3D misfolding of DNA," says senior author Benoit Bruneau. Next, the researchers want to find out when TBX5 first begins organizing the genome during development — and whether other proteins tied to birth defects shape DNA in similar ways.
