Two papers from the lab were published earlier this year. One from postdoc Luis Luna-Zurita, in a collaboration with Christoph Muller's lab, explores the interplay between heterotypic transcription factors, TBX5, NKX2-5, and GATA4 (all causative genes in human congenital heart disease) in cardiac differentiation. These interactions are complex, and serve not only to coordinately activate cell type-specific gene expression programs, but also act as locus tethers to prevent partner transcription factors from redistributing to ectopic loci resulting in inappropriate expression of genes that don't belong in a cardiac cell.
The second paper is from graduate student Siang-Yun Ang. This is a deep examination of the role of a histone methyltransferase, KMT2D (aka MLL2) that has been implicated in human congenital heart disease. Using several genetic deletions in the mouse, Yun found that KMT2D is important for activating a set of genes that fall into functional classes that include the excitation-contraction coupling machinery. By genome-wide analysis in embryonic heart, we found that the main role of KMT2D appears to be the addition of a dimethly group to lysine 4 of histone H3.
Together these papers explain unknown features of congenital heart disease-associated genes, and uncover new fundamental aspects of gene regulation.
Luna-Zurita L., Stirnimann C.U., Glatt S., Kaynak B.L., Thomas S., Baudin F., Samee Md.A.H., He D., Small E.M., Mileikovsky M., Nagy A., Holloway A.K., Pollard K.S., Muller C.W., & Bruneau B.G. (2016) Complex interdependence regulates heterotypic transcription factor distribution and coordinates cardiogenesis. *Cell 164:999-1014
Ang S.-Y., Uebersohn A., Spencer C.I., Huang Y., Lee J.-E., Ge K., & Bruneau B.G. (2016) KMT2D regulates specific programs in heart development via histone H3 lysine 4 dimethylation. Development* 143:810-821