Key result
NKX2-5 negatively regulates beta-catenin and positively regulates GATA4 in developing human cardiac myocytes by binding to specific elements in their promoter regions.
NKX2-5 directly modulates beta-catenin and GATA4 transcriptional activities in developing human cardiac myocytes, providing insight into the molecular pathways of cardiogenesis.
May inform cardiogenesis mechanisms; leaves open human in vivo validation and clinical translation.
BACKGROUND: The molecular pathway that controls cardiogenesis is temporally and spatially regulated by master transcriptional regulators such as NKX2-5, Isl1, MEF2C, GATA4, and beta-catenin. The interplay between these factors and their downstream targets are not completely understood. Here, we studied regulation of beta-catenin and GATA4 by NKX2-5 in human fetal cardiac myocytes. METHODOLOGY/PRINCIPAL FINDINGS: Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5. CONCLUSIONS: This study suggests that NKX2-5 modulates the beta-catenin and GATA4 transcriptional activities in developing human cardiac myocytes.
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Riazi et al. (2009) studied Cardiac development. NKX2-5 modulation (antisense RNA or overexpression) vs. Control vector (AdGFP) or wild type was evaluated on Expression levels of beta-catenin and GATA4. NKX2-5 negatively regulates beta-catenin and positively regulates GATA4 in developing human cardiac myocytes by binding to specific elements in their promoter regions.
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