Post-transcriptional mechanisms of gene regulation in cardiac cell growth and development

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 DESCRIPTION (provided by applicant): For many genes, steady state mRNA levels provide an inaccurate reflection of the extent to which they are translated into proteins. The factors influencing the translation of individual mRNAs during cardiac hypertrophy are poorly understood. Our objective is to determine the function of the cytosolic polyA-binding protein C1 (PABPC1) as a novel regulator of cardiac hypertrophy. PABPC1 selectively binds to the 3'- poly(A) tail sequence of most eukaryotic mRNAs and is critical for their overall translation and turnover. We demonstrate that PABPC1 protein levels in mice and humans are post-transcriptionally suppressed during postnatal heart development. Importantly, PABPC1 protein levels increase during cardiac hypertrophy, and we show that PABPC1 depleted mouse cardiac myocytes are resistant to pathologic hypertrophy. To directly test the role of PABPC1 in cardiac hypertrophy, we have developed a tetracycline-inducible and cardiac-specific PABPC1 transgenic mouse model. Further, we demonstrate that the poly(A) tail length of Pabpc1 mRNAs decreases during heart development, which is consistent with its reduced association with polysomes and poor translation. More significantly, we have discovered other stable, distinct, populations of short poly(A) tail containing mRNAs in adult hearts of mice and humans. The Specific Aims of this proposal are to: (1) Identify mechanism(s) that control cell-type specific expression of PABPC1; (2) Determine the requirement of PABPC1 in hypertrophic growth of cardiac cells; and (3) Determine the role of PABPC1 in modulating the poly(A) tail length and translation control of its target mRNAs in heart. We will use a combination of molecular, biochemical, transgenic and high-throughput sequencing approaches to address these important questions. PUBLIC HEALTH RELVANCE: This proposal will establish a new gene regulatory mechanism based on regulated changes in poly(A) tail length influencing the efficiency with which subset of cardiac mRNAs are translated. This project will also dissect the functional role of a poly(A) binding protein in stimulation of cardiac hypertrophy, a condition that is involved in number of heart diseases. Successful completion of the proposed research will produce detailed understanding of an unexplored mechanism of gene regulation and will open exciting new therapeutic opportunities to treat cardiac hypertrophy and its associated pathologies that affect millions of Americans.