Brd4 function in cardiac lineage commitment & morphogenesis

Tobacco smoke exposure during pregnancy is strongly associated with higher rates of congenital heart malformations and cigarette smoking is a major cause of heart attacks lending to the growing epidemic of heart failure. This proposal seeks to identify how a protein called Brd4, which has emerged as an important drug target for the treatment of cancer and heart failure, regulates the process by which heart-specific stem cells gives rise to heart muscle cells. Understanding the detailed molecular mechanisms of how a functional heart muscle cell is made during development holds the key to unlocking our ability to regenerate heart muscle cells in patients suffering from cardiovascular disease. Stem cells that make up the heart produce three different kinds of cells: myocytes (the muscle cells of the heart), endothelial cells (the cells that line blood vessels), and smooth muscle cells (the cells that surround and support blood vessels). How heart-specific stem cells decide which type of specialized cell they will become in the adult heart remains a mystery. Brd4 binds to specific modifications on histones (the proteins around which DNA is wrapped) that can affect how much a gene is turned on or off. My preliminary data suggests that Brd4 is important in promoting the development of heart muscle cells by helping to turn on specific sets of important genes. In the proposed work, I will use cell culture systems and mouse models to determine what happens to decision-making in heart stem cells when Brd4 is either inhibited by drugs or genetically deleted. Using cutting-edge sequencing technologies, I will define all of the genes that Brd4 is regulating during heart muscle cell development and uncover new genes that are essential for this process. Learning what makes a heart stem cell choose which type of specialized cell it will become is critical for our ability to create regenerative therapies for patients who have suffered heart attacks or have heart failure and for better understanding how these processes go awry in the setting of congenital heart disease.