Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/85530
Title: GATA6 cooperates with EOMES/SMAD2/3 to deploy the gene regulatory network governing human definitive endoderm and pancreas formation
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
Keywords: Science::Medicine
GATA6
Definitive Endoderm
Issue Date: 2019
Source: Chia, C. Y., Madrigal, P., Denil, S. L. I. J., Martinez, I., Garcia-Bernardo, J., El-Khairi, R., . . . Vallier, L. (2019). GATA6 cooperates with EOMES/SMAD2/3 to deploy the gene regulatory network governing human definitive endoderm and pancreas formation. Stem Cell Reports, 12(1), 57-70. doi:10.1016/j.stemcr.2018.12.003
Series/Report no.: Stem Cell Reports
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.
URI: https://hdl.handle.net/10356/85530
http://hdl.handle.net/10220/49231
DOI: 10.1016/j.stemcr.2018.12.003
Rights: © 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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