Human disease phenotypes associated with haploinsufficient gene requirements are often not recapitulated well in animal models. Here, we have investigated the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-mediated genome editing coupled with human pluripotent stem cell (hPSC) directed differentiation. We found that loss of one GATA6 allele specifically affects the differentiation of human pancreatic progenitors from the early PDX1+ stage to the more mature PDX1+NKX6.1+ stage, leading to impaired formation of glucose-responsive β-like cells. In addition to this GATA6 haploinsufficiency, we also identified dosage-sensitive requirements for GATA6 and GATA4 in the formation of both definitive endoderm and pancreatic progenitor cells. Our work expands the application of hPSCs from studying the impact of individual gene loci to investigation of multigenic human traits, and it establishes an approach for identifying genetic modifiers of human disease.
Pubmed ID: 28196600 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Software application with data analysis tools and spreadsheet templates to track and visualize data. It is used to manage and process data.
View all literature mentionsThis monoclonal targets beta-actin
View all literature mentionsThis polyclonal targets Phospho-Histone H3 (Ser10)
View all literature mentionsThis polyclonal targets Glucagon
View all literature mentionsThis polyclonal targets Cleaved Caspase-3 (Asp175)
View all literature mentionsThis monoclonal targets Glucagon
View all literature mentionsThis monoclonal targets insulin (proinsulin; C-peptide)
View all literature mentionsThis monoclonal targets Homeobox protein Nkx-6.1; Nkx6.1
View all literature mentionsThis polyclonal targets Human PDX-1/IPF1 Affinity Purified Ab
View all literature mentionsThis monoclonal targets GATA4
View all literature mentionsThis monoclonal targets GATA-6 (D61E4) XP Rabbit mAb
View all literature mentionsThis polyclonal targets Human SOX17
View all literature mentionsThis polyclonal targets HNF3beta/FOXA2
View all literature mentionsThis polyclonal targets POU5F1
View all literature mentions