MicroRNAs (miRNAs) negatively regulate gene expression by promoting mRNA degradation and inhibiting mRNA translation. Recent studies have uncovered key roles of miRNAs as mediators of cardiovascular development and disease, but much remains to be learned about their mechanisms of action and regulation. Dr. Olson's lab has described a family of muscle-specific miRNAs, referred to as MyomiRs, which are encoded by introns of myosin heavy chain genes. These three miRNAs (miR-208a, miR-208b, miR-499) control pathological cardiac remodeling, muscle myosin content, myofiber identity, and muscle performance. Each of these miRNAs regulates the expression of Sox6, a transcriptional repressor. Consistent with a role for Sox6 as a mediator of the actions of MyomiRs, over-expression of Sox6 in skeletal muscle mimics the effects of MyomiR gene deletion and deletion of Sox6 in skeletal muscle recapitulates the phenotype of MyomiR over-expression. These findings have revealed a previously unrecognized role for Sox6 as a mediator of skeletal muscle gene expression, but nothing is known of its potential role in the control of cardiac gene expression or function. Given the importance of MyomiRs in regulating cardiac stress responses, and the regulation of Sox6 expression by MyomiRs, we postulate that Sox6 is a central regulator of cardiac hypertrophy and heart failure. The goal of this project is to define the mechanisms whereby Sox6 controls cardiac gene expression by idenfication of its downstream target genes and transcriptional cofactors and to explore its role as a mediator of the actions of myosin-encoded cardiac miRNAs. The project will benefit from a strong foundation of preliminary data and unique mouse strains (e.g. Sox6 knockout and transgenic mice) already established in the lab. These studies promise to provide important new insights into the gene regulatory mechanisms in heart disease and to potentially reveal new therapeutic targets for modulation of cardiac function.