Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis

Abstract

SUMMARY Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.

A single cell transcriptional roadmap for cardiopharyngeal fate diversification

“…15, 2017; universally conserved pan-cardiac regulators Nk4/Nkx2-5, Gata4/5/6 and Hand (e.g. (Ang et al, 2016;Luna-Zurita et al, 2016;Tsuchihashi et al, 2011) .…”

Genome Editing in hPSCs Reveals GATA6 Haploinsufficiency and a Genetic Interaction with GATA4 in Human Pancreatic Development

“…Several hundred haploinsufficient genes, many of which encode transcription factors, have been reported to cause diverse disorders affecting the pancreas, heart, brain and other organs (Dang et al, 2008; Seidman and Seidman, 2002). For example, heterozygous inactivation of TBX5 , NKX2.5 or GATA4 are associated with dominantly inherited congenital heart defects (Ang et al, 2016; Bruneau, 2008), while HNF1A , HNF4A and HNF1B heterozygous loss-of-function mutations are each found in patients with a monogenic form of diabetes known as maturity onset diabetes of the young (MODY) (Ryffel, 2001). Notably, haploinsufficiency is typically associated with a wide spectrum of phenotypic manifestations, suggesting a significant contribution of modifier genes and/or non-genetic factors such as lifestyle and diet (Seidman and Seidman, 2002).…”

Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation

“…GATA4 and TBX5 interact physically to activate gene expression synergistically in the heart (2), and multiple Gata4 transcriptional targets have been identified in the heart (1,4,5,7,22,64). Recent studies have indicated that GATA4 and TBX5 are essential for each other's transcriptional fidelity in the control of cardiac gene regulatory networks in mouse and human models (65,66). Determining GATA4 and TBX5 coregulated targets in the SHF may identify genes essential for normal atrial septum morphogenesis.…”