Journal article
GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm
- Abstract:
- Damaging GATA6 variants cause cardiac outflow tract defects, sometimes with pancreatic and diaphragmic malformations. To define molecular mechanisms for these diverse developmental defects, we studied transcriptional and epigenetic responses to GATA6 loss of function (LoF) and missense variants during cardiomyocyte differentiation of isogenic human induced pluripotent stem cells. We show that GATA6 is a pioneer factor in cardiac development, regulating SMYD1 that activates HAND2, and KDR that with HAND2 orchestrates outflow tract formation. LoF variants perturbed cardiac genes and also endoderm lineage genes that direct PDX1 expression and pancreatic development. Remarkably, an exon 4 GATA6 missense variant, highly associated with extra-cardiac malformations, caused ectopic pioneer activities, profoundly diminishing GATA4, FOXA1/2, and PDX1 expression and increasing normal retinoic acid signaling that promotes diaphragm development. These aberrant epigenetic and transcriptional signatures illuminate the molecular mechanisms for cardiovascular malformations, pancreas and diaphragm dysgenesis that arise in patients with distinct GATA6 variants.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 7.2MB, Terms of use)
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- Publisher copy:
- 10.7554/elife.53278
Authors
- Publisher:
- eLife Sciences Publications
- Journal:
- eLife More from this journal
- Volume:
- 9
- Article number:
- e53278
- Publication date:
- 2020-10-15
- Acceptance date:
- 2020-10-14
- DOI:
- EISSN:
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2050-084X
- Language:
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English
- Keywords:
- Pubs id:
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1138167
- Local pid:
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pubs:1138167
- Deposit date:
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2020-10-18
Terms of use
- Copyright holder:
- Sharma et al.
- Copyright date:
- 2020
- Rights statement:
- © Copyright Sharma et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
- Licence:
- CC Attribution (CC BY)
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