ROLE OF CARDIAC SOX6

Deciphering the functions of Sox6 and myosin-encoded microRNAs in heart failure and hypertrophy

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

European researchers are investigating the role of transcription factors in heart remodelling and consequent heart failure.

Descrizione progetto (Article)

MicroRNAs (miRNAs) regulate gene expression by promoting messenger RNA (mRNA) degradation or inhibiting mRNA translation. The 'Deciphering the functions of Sox6 and myosin-encoded microRNAs in heart failure and hypertrophy' (ROLE OF CARDIAC SOX6) project is investigating the role of the muscle-specific miRNA target Sox6 in the heart.

A group of three miRNAs control pathological cardiac remodelling, muscle myosin content, myofibre identity, and muscle performance and they all target a transcriptional repressor, Sox6. The Sox6 gene is implicated in maintaining cardiac structure and function.

The researchers also looked at another member of the SoxD family of transcription factors, Sox5. In a genome-wide study, Sox6 and Sox5 genes are linked to blood pressure or heart rate and electrophysiological features, respectively.

Sox5/6 knockout (KO) mice had reduced cardiac function at baseline and were susceptible to cardiac failure after cardiac pressure overload. When the scientists looked at the individual cardiomyocytes (called cardiac muscle cells), they found shortened action potential duration in cardiomyocytes lacking both, Sox6 and Sox5, or cells lacking Sox5, only. In vivo, deletion of Sox5 but not of Sox6 resulted in decreased cardiac contractility.

ROLE OF CARDIAC SOX6 researchers discovered that between them, Sox6 and Sox5 regulate around 300 genes. The majority of them were upregulated in Sox5/6 KO hearts, which is in line with Sox5 and Sox6 being transcriptional repressors. The scientists are continuing their research into the genes that are significantly regulated by Sox5 and Sox6.

The project results promise to provide new insight into the genetic control of heart disease. Once unveiled, the genes can lead to the development of targeted therapies.