Congenital heart defects (CHDs) occur in about 1% of live births, and result in significant mortality and morbidity. We currently have very little understanding of the basis of CHDs. Transcription factors are key regulators of heart formation, and mutations in cardiac transcription factor genes can cause CHDs in humans. These findings have underscored the need for precise dosage of transcription factor proteins in the developing heart. It is of paramount importance to understand the molecular basis of decreased transcription factor dosage in disease, in order to be able to rationally design non-surgical therapies for CHDs. The function of transcription factors is intimately related to and regulated by the structure of chromatin at their target sites in the genome. Chromatin remodeling affects the accessibility and activity of transcription factors;this occurs largely via ATP-dependent chromatin remodeling complexes, which loosen nucleosomes to allow access to the transcriptional machinery. We have recently identified a component of the mammalian Swi/Snf (BAF) chromatin complex, called Baf60c, which is expressed primarily in the developing heart and has key roles in regulating several aspects of cardiac morphogenesis. This has established a new paradigm in transcriptional regulation, by adding an additional layer of regulation in the form of tissue-specific chromatin remodeling complexes. We hypothesize that Baf60c and BAF chromatin remodeling complexes play critical dose-dependent roles to integrate cardiac transcription factors in active regulation of crucial aspects of cardiac morphogenesis and lineage decisions The aims of the current proposal are: 1. To functionally define the tissue-specific and dosage-sensitive roles played by the cardiac-restricted BAF complex subunit Baf60c and the BAF complex in heart morphogenesis. This will be accomplished by cardiac-specific deletion of Baf60c and Brg1, the BAF complex ATPase. 2. To uncover the role of the BAF complex in lineage decisions in the anterior (secondary) heart field. This will be accomplished by anterior heart field-specific deletion of Baf60c and Brg1, along with genetic lineage tracing. 3. To identify the molecular basis of interactions between Baf60c and cardiac transcription factors. The knowledge generated by the results of each aim will be crucial to our understanding of heart patterning and the mechanisms underlying CHDs. The results obtained in this project will provide new and important insights into the causes of CHDs. We will discover new and important gene regulation pathways that form the heart, and importantly we will understand how these pathways are dysfunctional in human disease.
|Wythe, Joshua D; Dang, Lan T H; Devine, W Patrick et al. (2013) ETS factors regulate Vegf-dependent arterial specification. Dev Cell 26:45-58|
|Takeuchi, Jun K; Lou, Xin; Alexander, Jeffrey M et al. (2011) Chromatin remodelling complex dosage modulates transcription factor function in heart development. Nat Commun 2:187|
|Bruneau, Benoit G (2010) Epigenetic regulation of the cardiovascular system: introduction to a review series. Circ Res 107:324-6|
|Alexander, Jeffrey M; Bruneau, Benoit G (2010) Lessons for cardiac regeneration and repair through development. Trends Mol Med 16:426-34|
|Takeuchi, Jun K; Bruneau, Benoit G (2009) Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459:708-11|