| Abstract: |
Haploinsufficiency for GATA6 is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages. Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning. Furthermore, interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers, suggesting cooperative regulation of cardiac lineage gene accessibility. We show that modulating WNT and BMP inputs during the first 48 hr of cardiac differentiation is sufficient to partially rescue CPC and CM defects in GATA6 heterozygous and homozygous mutant hESCs. This study provides evidence of the regulatory functions for GATA6 directing human precardiac mesoderm patterning during the earliest stages of cardiogenesis to further our understanding of haploinsufficiency causing CHD and the co-occurrence of cardiac and other organ defects caused by human GATA6 mutations. © 2024, Bisson et al.; Congenital heart disease results in babies being born with structural defects to their hearts. It is one of the most common kind of human birth defects, yet its genetic causes remain poorly understood. Previous studies have identified a gene known as GATA6, which is sometimes altered in patients with the condition. As for most human genes, cells typically carry two GATA6 copies, each inherited from one parent. In many congenital heart disease patients, only one of the two copies of the gene presents harmful mutations. However, it has so far remained difficult to investigate in the laboratory how this genetic profile results in heart defects. To bypass these limitations, Bisson et al. used human stem cells derived from the early embryo (known as hESCs) that can become any tissue in the body, including the heart. The team genetically designed hESC lines carrying either one (heterozygous) or two (homozygous) mutant copies of GATA6. Experiments showed that homozygous cells failed to generate any cardiac cells, while those stemming from heterozygous cells were partially impaired. Further molecular analyses established that GATA6 acts early in development by regulating WNT and BMP, two signaling pathways that contribute to hESCs becoming heart cells. These findings indicate that embryos in which both copies of GATA6 are defective cannot generate heart cells, and therefore are not viable. They also suggest that modulating WNT and BMP pathways early during development may partially rescue heart defects in mutant embryos. Overall, the work by Bisson et al. offers a promising avenue for future research into congenital heart disease by providing researchers with hESC lines in which GATA6 is mutated. |
