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Title:Post-transcriptional regulation of poly(A) binding proteins direct multiple facets of cardiac development and hypertrophy
Author(s):Seimetz, Joseph W.
Director of Research:Kalsotra, Auinash
Doctoral Committee Chair(s):Kalsotra, Auinash
Doctoral Committee Member(s):Shapiro, David; Chen, Jie; Ceman, Stephanie; Procko, Erik
Department / Program:Biochemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):heart disease
post-transcriptional regulation
alternative polyadenylation
Abstract:Heart disease remains the leading cause of death in the United States. Despite what is known about the risk factors associated with heart disease, the molecular mechanisms are still largely ambiguous. Cardiomyocytes are the major cell type of the heart, making up 85% of its mass. In mammals, cardiomyocytes become post-mitotic shortly after birth, and from this point on, the heart increases in size almost exclusively through cellular hypertrophy of existing cardiomyocytes in a process termed maturational hypertrophy. A key process during the progression to heart failure is pathologic cardiac hypertrophy: the heart increases its size in response to a variety of prolonged, external stimuli. Similar to maturational hypertrophy, cellular hypertrophy of existing cardiomyocytes is responsible for the increase in size of the heart during disease. The healthy adult heart is unique from other tissues in that the rate of protein synthesis is dramatically lower than in most tissues and lower than the developing heart. However, during adult cardiac hypertrophy, translation rates increase. This suggests a dynamic, tissue specific mechanism for regulating translation rates in the mammalian heart. In this dissertation, the discovery and characterization of multiple mechanisms for regulating gene expression and translation in the heart are described. These post-transcriptional mechanisms are mediated through multiple poly(A) binding proteins—PABPC1 and PABPN1—at the 3’UTR and poly(A) tail of cardiac mRNAs to tune transcript specific and overall translation rates within the heart. These findings define a new paradigm for cardiac gene regulation with potential for broader implications across many physiologically relevant contexts. Regulated expression of PABPC1 through a post-transcriptional, poly(A) tail length-based mechanism tunes overall protein synthesis rates within the heart in response to maturational and hypertrophic cues. PABPC1 was determined to be both necessary and sufficient for driving cardiac translation and hypertrophy. PABPC1 exerts its effect on overall translation rates through its interaction with eIF4G to enable translation through the closed-loop model. In biochemical and transcriptome-wide studies, PABPN1 was determined to be a primary effector of post-transcriptional events of maturational and adult hypertrophy related genes through regulation of APA and poly(A) tail length, including that of Pabpc1. PABPN1 as well was determined to be both necessary and sufficient to stimulate cardiac translation and hypertrophy. High resolution, single-molecule RNA-FISH studies determined that PABPN1 expression is controlled through intron retention and nuclear sequestration. Taken together, this dissertation presents a comprehensive model for the regulation of cardiac protein synthesis and hypertrophy in a physiologic context through multiple post-transcriptional mechanisms.
Issue Date:2021-07-09
Rights Information:The contents of Chapter 4 are pending publication
Date Available in IDEALS:2022-01-12
Date Deposited:2021-08

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