Role of mRNA Modifications in Cardiac Remodeling

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Independent of the etiology, heart failure involves changes in cardiac structure, contractile dysfunction, as well as multiple genetic, and molecular alterations that impact heart function and patient survival. These changes have been referred to as cardiac remodeling. Changes in gene expression with up- or down-regulation of specific sets of genes play a fundamental role during the pathogenesis of heart failure. Recent research has unveiled the importance of reversible mRNA modifications on gene expression control. This work has suggested that in addition to epigenetic modifications of DNA, many modifications of mRNAs occur, some of which directly impact development, cell growth, metabolism, cellular survival, and intracellular signaling. The most prevalent internal modification on mRNA is N6-methyladenosine (m6A), but very recently N1-methyladenosine (m1A) was discovered as another mRNA modification regulating gene expression in mammalian mRNAs. m6A modification is installed by m6A writers, is reversed by erasers, and is read by m6A readers. This returns mRNA to a role as a central hub of information within the cell, serving as an information carrier, modifier, and attenuator for many biological processes, in addition to transferring the message from the DNA.The overall goal of this proposal is to show that reversible modifications in mRNAs represent a novel epigenetic hallmark with broad roles in fundamental cardiac physiology and pathophysiology. The innovation of this proposal is based on the first comprehensive characterization of mRNA modifications in different cardiac cell types in the heart. The proposal aims to delineate the critical importance of the mRNA methylation machinery in the heart and to demonstrate the effects of mRNA methylation on growth and survival. The significance of these studies is to define ways to blunt pathological remodeling, to improve cellular survival in cardiac diseases with the goal to delineate new therapeutic options for the treatment of heart failure.