Stat3 directly controls the expression of Tbx5, Nkx2.5, and GATA4 and is essential for cardiomyocyte differentiation of P19CL6 cells.

The transcription factor Stat3 (signal transducer and activator of transcription 3) mediates many physiological processes, including embryogenesis, stem cell self-renewal, and postnatal survival. In response to gp130 receptor activation, Stat3 becomes phosphorylated by the receptor-associated Janus kinase, forms dimers, and enters the nucleus where it binds to Stat3 target genes and regulates their expression. In this report, we demonstrate that Stat3 binds directly to the promoters and regulates the expression of three genes that are essential for cardiac differentiation: Tbx5, Nkx2.5, and GATA4. We further demonstrate that Tbx5, Nkx2.5, and GATA4 expression is dependent on Stat3 in response to ligand treatment and during ligand-independent differentiation of P19CL6 cells into cardiomyocytes. Finally, we show that Stat3 is necessary for the differentiation of P19CL6 cells into beating cardiomyocytes. All together, these results demonstrate that Stat3 is required for the differentiation of cardiomyocytes through direct transcriptional regulation of Tbx5, Nkx2.5, and GATA4.