GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm

  1. Arun Sharma
  2. Lauren K Wasson
  3. Jon AL Willcox
  4. Sarah U Morton
  5. Joshua M Gorham
  6. Daniel M DeLaughter
  7. Meraj Neyazi
  8. Manuel Schmid
  9. Radhika Agarwal
  10. Min Young Jang
  11. Christopher N Toepfer
  12. Tarsha Ward
  13. Yuri Kim
  14. Alexandre C Pereira
  15. Steven R DePalma
  16. Angela Tai
  17. Seongwon Kim
  18. David Conner
  19. Daniel Bernstein
  20. Bruce D Gelb
  21. Wendy K Chung
  22. Elizabeth Goldmuntz
  23. George Porter
  24. Martin Tristani-Firouzi
  25. Deepak Srivastava
  26. Jonathan G Seidman
  27. Christine E Seidman  Is a corresponding author
  1. Harvard Medical School, United States
  2. Universidade de São Paulo, Brazil
  3. Stanford Medical School, United States
  4. Mount Sinai School of Medicine, United States
  5. Columbia University, United States
  6. Children's Hospital of Philadelphia, United States
  7. University of Rochester, United States
  8. University of Utah, United States
  9. Gladstone Institutes, United States
  10. Brigham and Womens Hospital and Harvard Medical School, United States

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 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. Loss of function 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.

Data availability

All data generated or analyzed during this study are included in the manuscript.

The following previously published data sets were used

Article and author information

Author details

  1. Arun Sharma

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lauren K Wasson

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5193-5215
  3. Jon AL Willcox

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sarah U Morton

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Joshua M Gorham

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel M DeLaughter

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Meraj Neyazi

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Manuel Schmid

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Radhika Agarwal

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Min Young Jang

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Christopher N Toepfer

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Tarsha Ward

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Yuri Kim

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Alexandre C Pereira

    Instituto do Coração, Universidade de São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  15. Steven R DePalma

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Angela Tai

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Seongwon Kim

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. David Conner

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Daniel Bernstein

    Pediatrics, Stanford Medical School, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Bruce D Gelb

    Pediatrics, Mount Sinai School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Wendy K Chung

    Pediatrics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Elizabeth Goldmuntz

    Cardiology, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2936-4396
  23. George Porter

    Pediatrics, University of Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Martin Tristani-Firouzi

    Pediatrics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Deepak Srivastava

    Gladstone Institutes, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3480-5953
  26. Jonathan G Seidman

    Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9082-3566
  27. Christine E Seidman

    Medicine and Genetics, Brigham and Womens Hospital and Harvard Medical School, Boston, United States
    For correspondence
    cseidman@genetics.med.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6380-1209

Funding

National Institutes of Health (UM1HL128711)

  • George Porter
  • Martin Tristani-Firouzi
  • Deepak Srivastava
  • Jonathan G Seidman
  • Christine E Seidman

Howard Hughes Medical Institute

  • Tarsha Ward

National Institutes of Health (UM1HL128761)

  • Christine E Seidman

National Institutes of Health (UM1HL098147)

  • Daniel M DeLaughter

National Institutes of Health (U01-HL098153)

  • Jonathan G Seidman
  • Christine E Seidman

National Institutes of Health (U01-HL098163)

  • Jonathan G Seidman
  • Christine E Seidman

National Institutes of Health (U01-HL098123)

  • Jonathan G Seidman
  • Christine E Seidman

National Institutes of Health (U01-HL098162)

  • Jonathan G Seidman
  • Christine E Seidman

National Science Foundation (EEC-1647837)

  • Jonathan G Seidman
  • Christine E Seidman

National Institutes of Health (T32HL116273)

  • Arun Sharma

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Edward E Morrisey, University of Pennsylvania, United States

Ethics

Human subjects: CHD subjects were recruited to the Congenital Heart Disease Network Study of the Pediatric Cardiac Genomics Consortium (CHD GENES: ClinicalTrials.gov identifier NCT01196182) after approval from Institutional Review Boards as previously described (Pediatric Cardiac Genomics et al., 2013; Jin et al., 2017). Written informed consent was received from subjects or their parents prior to inclusion in the study. Clinical diagnoses were standardized based on review of medical data and family interviews.

Version history

  1. Received: November 1, 2019
  2. Accepted: October 14, 2020
  3. Accepted Manuscript published: October 15, 2020 (version 1)
  4. Version of Record published: October 28, 2020 (version 2)

Copyright

© 2020, Sharma et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Arun Sharma
  2. Lauren K Wasson
  3. Jon AL Willcox
  4. Sarah U Morton
  5. Joshua M Gorham
  6. Daniel M DeLaughter
  7. Meraj Neyazi
  8. Manuel Schmid
  9. Radhika Agarwal
  10. Min Young Jang
  11. Christopher N Toepfer
  12. Tarsha Ward
  13. Yuri Kim
  14. Alexandre C Pereira
  15. Steven R DePalma
  16. Angela Tai
  17. Seongwon Kim
  18. David Conner
  19. Daniel Bernstein
  20. Bruce D Gelb
  21. Wendy K Chung
  22. Elizabeth Goldmuntz
  23. George Porter
  24. Martin Tristani-Firouzi
  25. Deepak Srivastava
  26. Jonathan G Seidman
  27. Christine E Seidman
(2020)
GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm
eLife 9:e53278.
https://doi.org/10.7554/eLife.53278

Share this article

https://doi.org/10.7554/eLife.53278

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