GATA6 cooperates with EOMES/SMAD2/3 to deploy the gene regulatory network governing human definitive endoderm and pancreas formation

• Main Authors: Chia, Crystal Y., Madrigal, Pedro, Denil, Simon L.I.J., Martinez, Iker, Garcia-Bernardo, Jose, El-Khairi, Ranna, Chhatriwala, Mariya, Shepherd, Maggie H., Hattersley, Andrew T., Vallier, Ludovic, Dunn, Norris Ray
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2019
• Subjects: Science::Medicine; GATA6; Definitive Endoderm
• Online Access: https://hdl.handle.net/10356/85530; http://hdl.handle.net/10220/49231
• Institution: Nanyang Technological University

Heterozygous de novo mutations in GATA6 are the most frequent cause of pancreatic agenesis in humans. In mice, however, a similar phenotype requires the biallelic loss of Gata6 and its paralog Gata4. To elaborate the human-specific requirements for GATA6, we chose to model GATA6 loss in vitro by combining both gene-edited and patient-derived pluripotent stem cells (hPSCs) and directed differentiation toward β-like cells. We find that GATA6 heterozygous hPSCs show a modest reduction in definitive endoderm (DE) formation, while GATA6-null hPSCs fail to enter the DE lineage. Consistent with these results, genome-wide studies show that GATA6 binds and cooperates with EOMES/SMAD2/3 to regulate the expression of cardinal endoderm genes. The early deficit in DE is accompanied by a significant reduction in PDX1+ pancreatic progenitors and C-PEPTIDE+ β-like cells. Taken together, our data position GATA6 as a gatekeeper to early human, but not murine, pancreatic ontogeny.