Abstract
The transcription factors GATA4, GATA5 and GATA6 are important regulators of heart muscle differentiation (cardiomyogenesis), which function in a partially redundant manner. We identified genes specifically regulated by individual cardiogenic GATA factors in a genome-wide transcriptomics analysis. The genes regulated by gata4 are particularly interesting because GATA4 is able to induce differentiation of beating cardiomyocytes in Xenopus and in mammalian systems. Among the specifically gata4-regulated transcripts we identified two SoxF family members, sox7 and sox18. Experimental reinstatement of gata4 restores sox7 and sox18 expression, and loss of cardiomyocyte differentiation due to gata4 knockdown is partially restored by reinstating sox7 or sox18 expression, while (as previously reported) knockdown of sox7 or sox18 interferes with heart muscle formation. In order to test for conservation in mammalian cardiomyogenesis, we confirmed in mouse embryonic stem cells (ESCs) undergoing cardiomyogenesis that knockdown of Gata4 leads to reduced Sox7 (and Sox18) expression and that Gata4 is also uniquely capable of promptly inducing Sox7 expression. Taken together, we identify an important and conserved gene regulatory axis from gata4 to the SoxF paralogs sox7 and sox18 and further to heart muscle cell differentiation.
Highlights
Heart development and heart muscle differentiation is controlled by an intricate Gene Regulatory Network (GRN)
In this study we aimed to explore such gata genespecific functions more comprehensively using genome-wide transcriptomics analysis, in order to widen our general understanding of the gene regulatory network (GRN) directing cardiomyogenesis
Using gene knockdown approaches we have identified genes that are regulated by individual cardiogenic gata factor genes gata4, gata5 or gata6; as well as those regulated by either one of them, and those regulated by all three of them together
Summary
Heart development and heart muscle differentiation (cardiomyogenesis) is controlled by an intricate Gene Regulatory Network (GRN). This GRN involves prominent members of specific transcription factor gene families, such as the Nkx, Mef, Tbx and Gata gene families (Harvey and Rosenthal, 1999; Olson and Srivastava, 1996). Among these important transcription factors, GATA4, GATA5 and GATA6 are identified as the cardiogenic gata transcription factors Forced expression of Gata in mouse together with Tbx and the chromatin remodelling protein Baf60c can reprogram somatic mesoderm into heart muscle cells (Takeuchi and Bruneau, 2009); and combined expression of Gata with Tbx and Mef2c was reported to convert cultured fibroblastic cells into a cardiac lineage (Ieda et al, 2010)
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