GSE106335
Loss-of-function due to MODY1/HNF4A mutation abrogates liver and pancreas differentiation from MODY1-hiPSCs
Purpose: To investigate the impact of MODY1/HNF4A mutation on foregut development using differentiated control and MODY1-hiPSCs Methods: RNA-Seq was performed on foregut/hepato-pancreatic progenitors obtained on day 14 of the directed differentiation of hiPSCs from MODY1 patients (3 clones from iN904-1, 1 clone from iN904-2) and family controls (3 clones from iN904-7, 2 clones from iN904-13). Differential expression analysis, KEGG pathway and gene ontology analyses were carried out. qRT-PCR validation was also performed using SYBR Green assays. Results: RNA-Seq and transcriptional analyses revealed that numerous foregut liver- and pancreas-related genes, including HNF4A, were downregulated in MODY1-hiPSC-derived hepato-pancreatic progenitors with a fold change =1.5 and p value <0.05, whereas hindgut HOX genes were upregulated. Altered expression of a number of genes were further confirmed with qRT-PCR. Conclusions: The HNF4A loss-of-function mutation (p.Ile271fs) resulted in significantly reduced HNF4A expression or HNF4A haploinsufficiency, affecting the proper development of the foregut and its derivatives. This deficiency is propagated to both hepatic and pancreatic cell fates, and may account for ß cell developmental defects and the progressive deterioration of ß cell function in MODY1. Overall design: RNA-Seq was performed on foregut/hepato-pancreatic progenitors obtained on day 14 of the directed differentiation of hiPSCs from MODY1 patients (3 clones from iN904-1, 1 clone from iN904-2) and family controls (3 clones from iN904-7, 2 clones from iN904-13).