Hypertrophic growth of adult cardiac myocytes is a clinical manifestation of many cardiovascular disorders and is often a direct cause of heart failure. Occurring as a compensatory response to cardiac stress, it involves thickening of the heart muscle and reduction in the size of the heart chamber. Cardiac hypertrophy is associated with a return to a fetal gene expression program, which weakens cardiac function and promotes hypertrophic growth. In recent years, multiple studies have shown that chromatin structure plays important regulatory roles in the expression of cardiac genes and the growth of cardiac myocytes. For example, class I and class II histone deacetylases (HDACs) promote and repress cardiac hypertrophy, respectively. However, the roles of many other chromatin modifiers in the adult heart remain unclear. The Polycomb Group (PcG) and Trithorax Group (TrxG) proteins are highly conserved regulators of chromatin structure. The PcG proteins repress transcription by generating and maintaining the repressive histone mark, trimethylated histone H3 lysine 27 (H3K27me3). The TrxG proteins antagonize PcG function and activate transcription by trimethylating histone H3 lysine 4 (H3K4) and by mediating nucleosomal sliding. A third group of proteins, known as Enhancers of Trithorax and Polycomb (ETP), are thought to promote PcG and TrxG activities by help recruiting PcG and TrxG proteins to target chromating loci. Both PcG and TrxG activities are disrupted in mice mutant for the ETP gene Asxl2. During our characterization of the Asxl2 mutant mice, we found that Asxl2 mutant hearts display characteristics of cardiac hypertrophy and reactivate many fetal genes. We hypothesize that the disruption of PcG and TrxG activities in Asxl2 mutant mice may have caused the expression of fetal genes and the development of cardiac hypertrophy in these animals. The implication of the PcG/TrxG system in the regulation of cardiac hypertrophy is highly intriguing and holds a lot of potentials. This proposal describes three lines of experiments designed to directly assay the role of the PcG/TrxG system in the regulation of cardiac gene expression and myocyte growth. We plan to examine how cardiac stress impacts the PcG/TrxG system as well as how the loss of PcG/TrxG activity impacts gene expression and growth of cardiac myocytes. In addition, we will test whether small molecular inhibitors of PcG and TrxG activities alter the hypertrophic response of cardiac myocytes. This exploratory study may open a new direction in cardiac hypertrophy research and identify new targets for anti-hypertrophy drugs.
Cardiac hypertrophy occurs in 1 in 500 people and is often associated with heart failure. A thorough understanding of the molecular events that control the hypertrophic growth of adult cardiac myocytes is important for the prevention and treatment of cardiac hypertrophy. The PcG/TrxG system is a major system for transcriptional regulation and has been implicated in many developmental processes and diseases. This proposal sought to characterize the role of the PcG/TrxG system in transcriptional regulation and growth control of cardiac myocytes. The identification of new molecules and mechanisms that regulate cardiac myocyte growth will help open the door to new drugs and new therapies.
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