New paper on TBX5 dosage and 3D genome organization!

Our new paper, published in Science, explores how the dosage of TBX5, a transcription factor strongly linked to congenital heart disease, affects the three-dimensional organization of the human genome. Using human cardiomyocytes, we found that reducing TBX5 levels disrupts genome organization at multiple levels, including chromatin compartments, topologically associated domains, and chromatin loops. These changes were particularly evident at regions normally bound by TBX5, where reduced TBX5 was associated with decreased cohesin binding.

These findings reveal an important connection between transcription factor dosage and 3D genome organization, providing a potential new mechanism for how TBX5 haploinsufficiency can lead to congenital heart disease. The work also highlights how individual cells can respond differently to changes in transcription factor dosage, adding another layer of complexity to developmental disease.

Grant ZL, Kuang S, Zhang S, et al. Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor. Science. 2026;393(6809). doi:10.1126/science.adv5434.