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NKX2-5 regulates the expression of beta-catenin and GATA4 in ventricular myocytes.

  • Author(s): Riazi, Ali M;
  • Takeuchi, Jun K;
  • Hornberger, Lisa K;
  • Zaidi, Syed Hassan;
  • Amini, Fariba;
  • Coles, John;
  • Bruneau, Benoit G;
  • Van Arsdell, Glen S
  • Editor(s): Fugmann, Sebastian D
  • et al.
Abstract

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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