Heart failure, the leading cause of death in the United States, is thought to result from the prolonged effects of a compensatory remodeling process that results in eventual malfunction of the mechanically exhausted myocardium. The heart remodels itself by reverting to a “fetal” expression profile, defined by a sustained shift in isoforms of structural, electrophysiological, and metabolic proteins. Although this is a well recognized phenomenon, how the fetal expression profile is re-initiated and maintained is poorly understood. To this end, in our laboratory, a mouse model for neonatal-onset cardiomyopathy has been developed.
Mice lacking Sox6, a member of the Sox family of transcription factors, manifest three key features of the failing human heart all within a week of birth: 1) fetal isoform gene expression, 2) prolonged action potential duration, and 3) downregulation of K+ currents. Along with these observations, data from our lab suggest that Sox6 acts as a transcriptional repressor of fetal genes in the heart after birth. Therefore, understanding how the Sox6 protein regulates expression of fetal genes will help us to uncover the unknown molecular mechanisms of fetal gene reactivation in the failing heart.
Because of its lack of a “repressor” or “activator” domain, Sox6 requires cofactors to control transcription of its target genes. Because Sox6 cannot function alone, I hypothesize that these cofactors exert specific functional consequences on the ability of Sox6 to negatively regulate transcription of fetal genes in the postnatal heart, and that these interactions contribute to cardiac development, maintenance, and disease. To identify Sox6 cofactors, yeast two-hybrid screening has been applied and I have identified several candidate cofactors from a human heart cDNA library using one of the protein-protein interaction domains of the Sox6 protein. In this proposal, to test my central hypothesis, I will further identify and characterize Sox6 cofactors using other functional domains of the protein, and determine how these cofactors provide specificity to Sox6 function in the heart.
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