Mechanisms of YY1 Inhibition of Cardiac Hypertrophy

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DESCRIPTION (provided by applicant): Heart failure is the most expensive medical problem in the United States, and a major cause of death and disability. Although pharmacological inhibitors targeted to the treatment of heart failure are therapeutically beneficial, heart failure is still increasing in frequency, and additional targets are needed. Our long term goal is to define the molecular mechanism(s) by which the transcription factor YY1 protects against pathologic cardiac hypertrophy and to provide valuable targets for the prevention of cardiac disease. YY1 is an ubiquitous transcription factor that regulates expression of multiple genes. YY1 has been shown to be mostly a represser of muscle genes. We have strong preliminary data showing that YY1 prevents the cellular changes that accompany cardiac hypertrophy. YY1 prevents up-regulation of the fetal isoforms of gene expression in response to alpha and beta adrenergic stimulation by binding to and retaining in the nucleus class II histone deacetylases (HDACs). The goals of this application are to: (Aim I) identify the mechanism by which YY1 prevents HDACs 4 and 5 nuclear export in response to various hypertrophic agonists; (Aim II) analyze the interaction of YY1 with fetal gene promoters in response to various hypertrophic stimuli (Aim III) characterize the effect of YY1 over-expression in an in vivo model system of pathological cardiac hypertrophy. Aim I will be achieved by analyzing YY1-HDAC interaction domains; constructs containing the interaction domains will be transfected into neonate cardiac myocytes and gene expression, cellular hypertrophy and HDACs 4 and 5 localization will be analyzed. Aim II will be achieved through chromatin immunoprecipitation of YY1 and the various fetal gene promoters in response to hypertrophic stimuli. Aim IV will be achieved by creating a conditional transgenic mouse model of YY1 over-expression. Hypertrophy will be induced in these animals by implantation of mini-osmotic pumps containing hypertrophic agonists, and heart function and changes in cellular hypertrophy will be analyzed. The data revealed from these studies will rapidly progress our understanding of the signaling components responsible for the development of pathologic cardiac hypertrophy.