GATA factors efficiently direct cardiac fate from embryonic stem cells

Abstract

SUMMARYThe GATA4 transcription factor is implicated in promoting cardiogenesis in combination with other factors, including TBX5, MEF2C and BAF60C. However, when expressed in embryonic stem cells (ESCs), GATA4 was shown to promote endoderm, not cardiac mesoderm. The capacity of related GATA factors to promote cardiogenesis is untested. We found that expression of the highly related gene, Gata5, very efficiently promotes cardiomyocyte fate from murine ESCs. Gata5 directs development of beating sheets of cells that express cardiac troponin T and show a full range of action potential morphologies that are responsive to pharmacological stimulation. We discovered that by removing serum from the culture conditions, GATA4 and GATA6 are each also able to efficiently promote cardiogenesis in ESC derivatives, with some distinctions. Thus, GATA factors can function in ESC derivatives upstream of other cardiac transcription factors to direct the efficient generation of cardiomyocytes.

Pax3 and Tbx5 Specify Whether PDGFRα+ Cells Assume Skeletal or Cardiac Muscle Fate in Differentiating Embryonic Stem Cells

“…As expected, this list contains genes that had already been reported to be expressed in the cardiac crescent in mouse (Vsnl1 and Gata5) or frog (Phox2a) developing embryos . Gata5, in association with Gata4 and Gata6, is important for proper cardiac development, and its over‐expression in ESCs differentiated, in serum‐free conditions, efficiently promotes cardiac fate . Importantly, our screening identified a Tbx5‐dependent upregulation of Gata4 and Gata5 in cells from day 5 EBs, which suggests a positive correlation between Tbx5 and Gata4/5 expression.…”

“…These processes are regulated by several transcription factors which, if mutated or absent, lead to cardiac malformations in both mice and humans . Due to the ability of mesodermal precursors (MES) to change fate based on the expression of lineage‐specific master regulators , Pax3‐induced repression of the cardiac program may be the result of the downregulation of important key regulators of cardiac myogenesis. To gain better insight into the nature of this process, we analyzed how Pax3 represses the cardiac program during embryoid body (EB) differentiation and characterized gene expression in different mesodermal subfractions.…”

A gene regulatory program controlling early Xenopus mesendoderm formation: Network conservation and motifs

“…In zebrafish, loss of gata5 downregulates the expression of gata6 and vice versa [109]. Overexpression of Gata4, Gata5, or Gata6 in mouse ES cells results in the upregulation of all three factors [104,105,111], and Gata4 -null mice show reduced Gata6 expression [112]. …”

Dynamics of Cardiomyocyte Transcriptome and Chromatin Landscape Demarcates Key Events of Heart Development

“…Specification 71 and differentiation of the cardiac progenitors are regulated by the interactions between several key 72 TFs -Nkx2.5, Gata5, Tbx5, and Hand2. Members of the GATA family of TFs, Gata4, Gata5, and 73Gata6, are responsible for the earliest step of cardiac progenitor specification (Jiang and Evans 1996; 74 Jiang et al 1998;Reiter et al 1999;Singh et al 2010;Lou et al 2011;Turbendian et al 2013). Gata 75 factors activate the expression of nkx2.5, another early marker of CMs (Chen and Fishman 1996; Lien 76 et al 1999).…”