The transcriptional coactivator and histone acetyltransferase p300 was originally identified as a cellular target of adenovirus E1A, and has been implicated in many basic cell functions including proliferation, differentiation and tissue-specific gene expression. Others and we have shown that myocardial growth, development, and gene expression are extremely sensitive to p300 levels. Myocardial hypertrophy is associated with marked increases in p300 levels. To investigate the significance of this increase, we have generated 6 strains of transgenic mice with myocardial overexpression of p300 (1.5 to 5-fold of endogenous levels). All 6 strains develop severe cardiac hypertrophy, and progress to heart failure in a manner that is proportionate to their p300 levels and cardiac workload. Mice with haploinsufficiency of p300 have a markedly reduced hypertrophic response to pressure overload, and do not develop heart failure. These findings indicate that p300 plays a critical role in the induction of hypertrophy and the transition to heart failure. The objective of this proposal is to identify the molecular mechanisms underlying the role of p300 in hypertrophy. A widely accepted model for p300 function predicts that transcription factors compete for a limiting supply of p300. For example, Jun (AP-1) and MyoD1 engage in competitive transcription activation depending on the availability of p300. The current proposal will test the hypothesis that an increase in p300 supply is both sufficient and necessary for hypertrophic growth of the myocardium, through relief of a competitive interaction between growth-promoting and muscle-specific transcription programs. A corollary is that sustained activation of p3OO-dependent growth pathways leads to disordered myocardial growth and apoptosis. The requirement for p300 in hypertrophy will be tested in complementary mouse strains expressing inducible, cardiac-restricted wild type and specific domain-deleted p300 transgenes. We will characterize the functions and regulatory motifs of myocardial genes targeted by p300 in vivo, by the concerted use of genome-wide transcription profiling, chromatin immunoprecipitation assays, and quantitative RNA analysis, in mice with p300 gain- and loss-of-function. Finally, we will examine the functional effects of p300 availability on cardiomyocyte proliferation and apoptosis susceptibility. These experiments will identify critical mechanisms underlying cardiac hypertrophy and failure, and illuminate the role of p300 in hypertrophic growth of the cell.
Showing the most recent 10 out of 25 publications
