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

Graham, Nicola, Kirilenko, Pavel, Patrushev, Ilya, Fowler, Ewan D., Kille, Peter ORCID: https://orcid.org/0000-0001-6023-5221, Gilchrist, Michael, Owens, Nick D. L. and Latinkic, Branko ORCID: https://orcid.org/0000-0003-4952-123X 2026. Conserved roles of GATA4 and its target gene TBX2 in regulation of human cardiogenesis. Biology Open 15 (6) , bio.062553. 10.1242/bio.062553

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Biosciences
Publisher:	The Company of Biologists
ISSN:	2046-6390
Funders:	British Heart Foundation, Wellcome Trust
Projects:	PG/11/115/29287, FS/18/42/33827, FS/IBSRF/21/25071, 227357/Z/23/Z
Date of First Compliant Deposit:	27 May 2026
Date of Acceptance:	28 April 2026
Last Modified:	17 Aug 2026 13:40
URI:	https://orca.cardiff.ac.uk/id/eprint/187236

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