Biol Open 2026 May 15; doi: 10.1242/bio.062553.

Conserved roles of GATA4 and its target gene TBX2 in regulation of human cardiogenesis.

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The transcription factor (TF) GATA4 is a key mediator of cardiogenesis. GATA4 regulates cardiogenesis through the expression of its target genes, only some of which have been identified. We have used a gain of function model based on pluripotent embryonic ectoderm explants from Xenopus embryos expressing GATA4, to identify a set of downstream targets of GATA4 which are also regulated by Nodal, a known cardiogenic signal. GATA4 was shown to be required for the expression of target genes tbx2 and prdm1 in vivo, likely acting in a direct fashion by interacting with their regulatory regions. In addition, tbx2 and prdm1 are shown to have roles of their own in vivo, as downregulation of tbx2, a positive target, and overexpression of prdm1, a negative target, interferes with cardiac development in Xenopus embryos. The conservation of the GATA4-TBX2-PRDM1 regulatory relationship was shown in human iPSC-derived cardiomyocytes. Loss of function of GATA4 lead to downregulation of TBX2, upregulation of PRDM1 expression and failure of cardiogenesis. GATA4-deficient cells failed to form normal cardiomyocytes, with most cells adopting alternative fates and only a small minority expressing an aberrant cardiomyocyte phenotype. Genome-wide transcriptomic analysis documented severe reduction of cardiomyocyte and endothelial cell transcriptomes and upregulation of transcriptional profiles of smooth muscle cells and fibroblasts. Disruption of TBX2 function did not alter cardiomyocyte differentiation efficiency but led to the formation of cardiomyocytes with hypertrophic-like features consistent with maladaptive remodelling. The phenotype of these cells was characterised by defective sarcomeres and deficient calcium signalling. In addition, we show that whilst PRDM1 is not essential for formation of cardiomyocytes it is implicated in fine-tuning the timing and levels of gene expression. The results presented establish a conserved regulatory relationship between GATA4 and its target genes TBX2 and PRDM1 and roles for these genes in the modulation of cardiomyocyte development, expanding the cardiac gene regulatory network and providing further insight into how cardiogenesis proceeds.

???displayArticle.pubmedLink??? 42136535
???displayArticle.link??? Biol Open
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Species referenced: Xenopus laevis
Genes referenced: calb1 ccndx epha4 fst fzd8 gata2 gata4 gata6 hhex hoxc13 id2 id3 id4 igf2 lefty1 lmo2 map3k12 nodal5 osr1 osr2 plk2 prdm1 rgl2 rgs2 sox17a sox17b tbx2 tbx5 tnfsf10l trim29 usp43
GO keywords: heart development
???displayArticle.antibodies??? Gata4 AB1 HA High Affinity AB15 Mapk1 Ab9 Mybpc3 AB1 Pou3f5 Ab5 Prdm1 Ab1 Sox2 Ab1 Tbx2 Ab2 Tnnt2 AB5 Tubb Ab1
???displayArticle.morpholinos??? gata4 MO1 gata4 MO4 gata5 MO1 gata5 MO2 tbx2 MO2