Transcriptional Regulation of Heart Development and Function
- Author(s): Lu, Fei
- Advisor(s): Chen, Jau-Nian
- et al.
Cardiac morphogenesis and the maintenance of cardiac physiology require complex and well-orchestrated cardiac transcription programs. Misregulation of cardiac transcription programs leads to severe developmental defects, and is associated with human congenital heart diseases (CHD). To better understand the transcription program governing normal heart development, my research focused specifically on two essential genes for vertebrate heart development: tbx20 that encodes a cardiac transcription factor and rtf1 that encodes a multifunctional transcription regulatory protein. First, I reported the identification of a zebrafish tbx20 null mutation that causes severe cardiac progenitor defects, highlighting a previously unappreciated role for Tbx20 in promoting vertebrate cardiogenesis. I also revealed a novel function of Tbx20 in enhancing cardiomyocyte proliferation as a transcriptional activator. Second, I found that loss of Rtf1, a RNA polymerase II associated factor 1 (PAF1C) complex component, suppresses the cardiac transcription program and prevents the formation of cardiac progenitors. I discovered that Rtf1 controls cardiac progenitor formation and heart tube morphogenesis via two independent mechanisms: Rtf1 pushes multi-potent mesodermal cells to a cardiac fate through activating the cardiac transcription program and Rtf1 supports cardiomyocyte differentiation and heart tube morphogenesis by modulating the epigenome. Lastly, I found that cardiomyocyte-specific ablation of rtf1 in adult mouse heart leads to dilated cardiomyopathy and heart failure. Expression of genes encoding lipid metabolism related proteins, myofibrillar proteins, mitochondrial proteins and ion channels were significantly downregulated in rtf1-deficent hearts, suggesting that Rtf1 is an important regulator of the cardiac gene program that maintains myofibril integrity and cardiac function. Taken together, my studies provide new insights into the regulation of cardiac transcription program in developing and mature myocardium, and presents new candidate genes for CHD and cardiac dysfunction in humans.