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.
Keywords:
GATA6; definitive endoderm; disease modeling; human pluripotent stem cells; pancreatic agenesis.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation*
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Cell Lineage
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Cells, Cultured
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Endoderm / cytology
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Endoderm / metabolism*
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GATA6 Transcription Factor / genetics*
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GATA6 Transcription Factor / metabolism
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Gene Regulatory Networks*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Insulin-Secreting Cells / cytology
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Insulin-Secreting Cells / metabolism*
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Pancreas / abnormalities*
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Pancreas / metabolism
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Pancreatic Diseases / congenital*
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Pancreatic Diseases / genetics
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Pancreatic Diseases / metabolism
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Pluripotent Stem Cells / cytology
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Pluripotent Stem Cells / metabolism*
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Protein Binding
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Smad2 Protein / genetics
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Smad2 Protein / metabolism
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism
Substances
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EOMES protein, human
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GATA6 Transcription Factor
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GATA6 protein, human
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Homeodomain Proteins
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SMAD2 protein, human
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SMAD3 protein, human
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Smad2 Protein
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Smad3 Protein
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T-Box Domain Proteins
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Trans-Activators
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pancreatic and duodenal homeobox 1 protein
Supplementary concepts
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Pancreatic Agenesis, Congenital