Decoding the Cardiac Message

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Our understanding of the molecular underpinnings of cardiac development and stress-response has progressed non-linearly over the past 40 years. Preliminary observations that cardiac RNA content increases along with muscle mass in hypertrophy were followed in the 1980s by an explosion of information derived from the fruits of cDNA cloning: The use of individual gene-specific cDNA probes for spatio-temporal analysis of gene expression lead to the description of cardiac myosin and actin isoform mRNA regulation by thyroid hormone. Recombinant expression systems were developed as platforms for functional analyses of cDNA products. Assays of muscle-specific mRNAs after cellular manipulation revealed that intracellular proteins regulate gene transcription. The subsequent decades defined specific cis DNA elements and transactivating protein factors that reprogram individual cardiac genes in disease, and transcriptional profiling by microarray or RNA sequencing revealed genome-wide mRNA regulation under pathological conditions. However, the underlying mechanistic concepts about how mRNA expression is regulated did not change. Now, we are witnessing a second molecular revolution catalyzed by the recent observation that cytoplasmic microRNAs directly regulate mRNAs. Whereas transcriptional regulation is more “on” or “off” for a single gene, a single microRNA can fine-tune entire biological pathways according to physiological demand by partially suppressing or destabilizing multiple functionally related mRNAs. Concomitant transcriptional regulation of microRNAs and their mRNA targets in cardiac disease enhances diversity of response, but deconvoluting these interactions is a challenge to defining the role of microRNAs in heart disease. Understanding the determinants of microRNA-mRNA targeting will accelerate rational development of microRNA-based therapeutics.