Towards Understanding the Gene-Specific Roles of GATA Factors in Heart Development: Does GATA4 Lead the Way?

Abstract

Transcription factors play crucial roles in the regulation of heart induction, formation, growth and morphogenesis. Zinc finger GATA transcription factors are among the critical regulators of these processes. GATA4, 5 and 6 genes are expressed in a partially overlapping manner in developing hearts, and GATA4 and 6 continue their expression in adult cardiac myocytes. Using different experimental models, GATA4, 5 and 6 were shown to work together not only to ensure specification of cardiac cells but also during subsequent heart development. The complex involvement of these related gene family members in those processes is demonstrated through the redundancy among them and crossregulation of each other. Our recent identification at the genome-wide level of genes specifically regulated by each of the three family members and our earlier discovery that gata4 and gata6 function upstream, while gata5 functions downstream of noncanonical Wnt signalling during cardiac differentiation, clearly demonstrate the functional differences among the cardiogenic GATA factors. Such suspected functional differences are worth exploring more widely. It appears that in the past few years, significant advances have indeed been made in providing a deeper understanding of the mechanisms by which each of these molecules function during heart development. In this review, I will therefore discuss current evidence of the role of individual cardiogenic GATA factors in the process of heart development and emphasize the emerging central role of GATA4.

Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review

“…Many cardiac-specific genes possess GATA elements in their regulatory regions, including not only structural sarcomere genes, such as myosin light chain-3 (MYL3) or troponin C (TNNC1) and I (TNNI3), but also genes for Na + /Ca 2+ -exchanger (SLC8A3), acetylcholine receptor-M2 (CHRM2), cardiac-restricted ankyrine repeat protein (CARP), carnitine palmitoyltransferase-1b (CPT1B), and other transcription factors, such as NKX2-5, which have been shown to be regulated by GATA4 [52]. Due to the overlap in the DNAbinding region, the cardiac subfamily of GATA transcription factors (GATA4/5/6) exhibit redundant functions and interact with each other to ensure the specification of cardiac cells and subsequent heart development [53].…”

“…The endocardium and endocardial cushions have a high expression of the transcription factor, and it was shown that GATA4 mediates both epithelial-to-mesenchymal transition (EMT) in the endocardial cushions and the growth and remodeling of the atrioventricular cushions, playing an important role in valve development [57]. Furthermore, GATA4 interacts with different cofactors in order to promote cell-type-specific gene expression programs [53]. For example, Kim et al demonstrated the interaction between GATA4 and RERE (arginine-glutamic acid dipeptide repeats gene), a cardiac-expressed nuclear receptor co-regulator, in the development of the membranous portion of the ventricular septum, via their effects on EMT and mesenchymal cell proliferation [58].…”

Somatic GATA4 mutation contributes to tetralogy of Fallot

“…Recent aggregating evidence has underscored the key roles of some nuclear transcriptional factors in regulating proper cardiovascular morphogenesis, including the guanine-adenine-thymine-adenine (GATA) family of transcriptional factors ( 2 , 51 , 76 ). At present, six members of the GATA family have been categorized fundamentally into a cardiac subfamily (GATA4/5/6) and a hematopoietic subfamily (GATA1/2/3) ( 76 ).…”

“…Recent aggregating evidence has underscored the key roles of some nuclear transcriptional factors in regulating proper cardiovascular morphogenesis, including the guanine-adenine-thymine-adenine (GATA) family of transcriptional factors ( 2 , 51 , 76 ). At present, six members of the GATA family have been categorized fundamentally into a cardiac subfamily (GATA4/5/6) and a hematopoietic subfamily (GATA1/2/3) ( 76 ). GATA4 and GATA6 , as well as GATA5 , are among the first genes expressed abundantly in the embryonic heart with a partially overlapping mode of expression spectrum, and these three cardiogenic GATA factors regulate cardiac organogenesis ( 76 ).…”

“…At present, six members of the GATA family have been categorized fundamentally into a cardiac subfamily (GATA4/5/6) and a hematopoietic subfamily (GATA1/2/3) (76). GATA4 and GATA6, as well as GATA5, are among the first genes expressed abundantly in the embryonic heart with a partially overlapping mode of expression spectrum, and these three cardiogenic GATA factors regulate cardiac organogenesis (76). In addition, germline mutations in all three cardiogenic GATA genes (GATA4/5/6) are associated with various forms of congenital heart disease, including TOF (77)(78)(79)(80)(81), the most prevalent type of cyanotic birth defect with an estimated prevalence of 3/10,000 in live newborns (46).…”