Congenital heart disease is the most common birth defect. About 1 in 100 babies are born with it. One cause is a problem with a gene called TBX5, which helps build the heart. Some children have only one working copy of TBX5 instead of the usual two.
Scientists have wondered why losing just one copy can hurt heart growth. New research shows TBX5 does more than turn other genes on. It also helps fold DNA into a shape that heart cells need.
How DNA Folding Helps Cells Work
DNA is a very long instruction book. The cell folds it tightly, but not randomly. Each cell type folds DNA in its own way, so a heart cell reads different instructions than a brain cell.
The 3‑D shape has big sections, smaller domains, and loops. Loops bring far‑away switches called enhancers close to the genes they control.
Mapping the Heart’s 3D Genome
Researchers turned human stem cells into heart muscle cells. Some cells had two good copies of TBX5, some had one, and some had none. They used high‑resolution tools to map the DNA loops.
TBX5 Acts as an Architect
As the cells grew, large parts of DNA changed from “off” to “on.” TBX5 guided a protein called cohesin to the right spots, helping it make loops that connect genes with their enhancers.
When TBX5 was missing, the loops did not form well. DNA folded incorrectly, and important heart genes stayed silent. Even half the normal amount of TBX5 caused these problems.
Different heart cells reacted in slightly different ways. This may explain why people with the same TBX5 mutation can have varied heart defects.
Wider Impact on Developmental Disorders
The study suggests that other birth defects might also come from DNA mis‑folding, not just from broken gene instructions.
Future work will look at when TBX5 starts shaping DNA in the early heart and whether other disease‑linked proteins act in a similar way.
About the Study
The research was published in the journal Science. It was funded by the National Institutes of Health and several other organizations.