- Developmental Biology (Editorial Board)
Bruneau’s laboratory demonstrated the interactions between three disease-related transcription factors—TBX5, NKX2-5, and GATA4—at a genome scale. They found that these proteins co-localize across the genome to regulate the cardiac gene expression program, and elucidated some of the rules by which they co-recruit one another to active cardiac enhancers. The scientists also identified a protein-protein interaction that facilitates their shared binding, through the crystal structure of TBX5, NKX2-5, and their shared DNA binding site.
In addition, the team studied the roles played by another transcription factor, CTCF, in embryonic stem cells. Using a new system that allows rapid and reversible depletion of CTCF, they showed that the three-dimensional organization of chromatin into structures called “topologically associated domains” is highly dependent on CTCF. Through these studies, they discovered new rules about chromatin organization and how it impacts gene regulation.
They also examined the importance of a disease-related histone-modifying enzyme called KMT2D. The gene that encodes this protein is often mutated in congenital heart disease. They deleted KMT2D in mice and showed that it controls a set of genes essential for embryonic cardiac function by depositing at regulatory elements in the genome a specific type of histone modification that helps genes become activated.