GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm.

Arun Sharma,Meraj Neyazi,Radhika Agarwal,Seongwon Kim,Yuri Kim,Daniel Bernstein,Angela Tai,Manuel Schmid,Min Young Jang,Tarsha Ward,Elizabeth Goldmuntz,Deepak Srivastava,Alexandre C Pereira ,Sarah U Morton ,Steven R Depalma ,Bruce D Gelb ,George A Porter ,Jonathan G Seidman ,Daniel M Delaughter ,Lauren Wasson ,David A Conner ,Jon A L Willcox ,Martin Tristani‐Firouzi ,Christopher N Toepfer ,Wendy K Chung ,Joshua M Gorham ,Christine E Seidman

doi:10.7554/elife.53278

Abstract

Damaging GATA6 variants cause cardiac outflow tract defects, sometimes with pancreatic and diaphragmic malformations. To define molecular mechanisms for these diverse developmental defects, we studied transcriptional and epigenetic responses to GATA6 loss of function (LoF) and missense variants during cardiomyocyte differentiation of isogenic human induced pluripotent stem cells. We show that GATA6 is a pioneer factor in cardiac development, regulating SMYD1 that activates HAND2, and KDR that with HAND2 orchestrates outflow tract formation. LoF variants perturbed cardiac genes and also endoderm lineage genes that direct PDX1 expression and pancreatic development. Remarkably, an exon 4 GATA6 missense variant, highly associated with extra-cardiac malformations, caused ectopic pioneer activities, profoundly diminishing GATA4, FOXA1/2, and PDX1 expression and increasing normal retinoic acid signaling that promotes diaphragm development. These aberrant epigenetic and transcriptional signatures illuminate the molecular mechanisms for cardiovascular malformations, pancreas and diaphragm dysgenesis that arise in patients with distinct GATA6 variants.

Highlights

Congenital heart disease (CHD), the leading birth defect worldwide that occurs in approximately 1% of newborns (van der Linde et al, 2011), comprises a range of structural malformations arising during embryonic development (Zaidi and Brueckner, 2017)
Among Pediatric Cardiac Genomics Consortium (PCGC) CHD patients and 61 previously reported CHD patients with pathogenic GATA6 variants (Figure 1B) there were a preponderance of outflow tract malformations, including persistent truncus arteriosus, double-outlet right ventricle, tetralogy of Fallot, as well as aortic and pulmonary valve and septation defects (Kelly, 2012)
We considered whether the distribution of these 70 damaging GATA6 variants (61 published, 9 PCGC) across the 595 encoded GATA6 amino acids correlated with clinical phenotypes (Figure 1; Supplementary file 1A, B)

Summary

Introduction

Congenital heart disease (CHD), the leading birth defect worldwide that occurs in approximately 1% of newborns (van der Linde et al, 2011), comprises a range of structural malformations arising during embryonic development (Zaidi and Brueckner, 2017). GATA6, while expressed in the first heart field (Morrisey et al, 1996), plays critical roles in the developing second heart field (Molkentin, 2000) and in recruitment of cardiac neural crest lineages (Lepore et al, 2006) that together shape the cardiac outflow tract. Consistent with these developmental functions, CHD patients with GATA6 mutations have a striking preponderance of outflow tract malformations (Gharibeh et al, 2018; Kodo et al, 2009; Maitra et al, 2010). Integrating these datasets with clinical phenotypes observed in CHD patients with pathogenic GATA6 variants, we demonstrate how disrupted molecular programs cause aberrant development of the cardiac outflow tract, pancreas, and diaphragm

Results

Discussion

Materials and methods

Funding Funder National Institutes of Health