Abstract：
: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.
journal_name
Stem Cell Reportsjournal_title
Stem cell reportsauthors
Chia CY,Madrigal P,Denil SLIJ,Martinez I,Garcia-Bernardo J,El-Khairi R,Chhatriwala M,Shepherd MH,Hattersley AT,Dunn NR,Vallier Ldoi
10.1016/j.stemcr.2018.12.003subject
Has Abstractpub_date
2019-01-08 00:00:00pages
57-70issue
1issn
2213-6711pii
S2213-6711(18)30522-8journal_volume
12pub_type
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