THE GATA-4 TRANSCRIPTION FACTOR TRANSACTIVATES THE CARDIAC MUSCLE-SPECIFIC TROPONIN-C PROMOTER-ENHANCER IN NONMUSCLE CELLS

The unique contractile phenotype of cardiac myocytes is determined by the expression of a set of cardiac muscle-specific genes. By analogy t o other mammalian developmental systems, it is likely that the coordin ate expression of cardiac genes is controlled by lineage-specific tran scription factors that interact with promoter and enhancer elements in the transcriptional regulatory regions of these genes. Although previ ous reports have identified several cardiac muscle-specific transcript ional elements, relatively little is known about the lineage-specific transcription factors that regulate these elements. In this report, we demonstrate that the slow/cardiac muscle-specific troponin C (cTnC) e nhancer contains a specific binding site for the lineage-restricted zi nc finger transcription factor GATA-4 This GATA-4-binding site is requ ired for enhancer activity in primary cardiac myocytes. Moreover, the cTnC enhancer can be transactivated by overexpression of GATA-4 in non -cardiac muscle cells such as NIH 3T3 cells. In situ hybridization stu dies demonstrate that GATA-4 and cTnC have overlapping patterns of exp ression in the hearts of postimplantation mouse embryos and that GATA- 4 gene expression precedes cTnC expression. Indirect immunofluorescenc e reveals GATA-4 expression in cultured cardiac myocytes from neonatal rats. Taken together, these results are consistent with a model in wh ich GATA-4 functions to direct tissue-specific gene expression during mammalian cardiac development.