دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm.
المؤلفون: Sharma A; Department of Genetics, Harvard Medical School, Boston, United States.; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, United States.; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, United States., Wasson LK; Department of Genetics, Harvard Medical School, Boston, United States.; Howard Hughes Medical Institute, Harvard Medical School, Boston, United States., Willcox JA; Department of Genetics, Harvard Medical School, Boston, United States., Morton SU; Department of Genetics, Harvard Medical School, Boston, United States.; Division of Newborn Medicine, Boston Children's Hospital, Boston, United States., Gorham JM; Department of Genetics, Harvard Medical School, Boston, United States., DeLaughter DM; Department of Genetics, Harvard Medical School, Boston, United States., Neyazi M; Department of Genetics, Harvard Medical School, Boston, United States.; Hannover Medical School, Hannover, Germany., Schmid M; Department of Genetics, Harvard Medical School, Boston, United States.; Deutsches Herzzentrum München, Technische Universität München, Munich, Germany., Agarwal R; Department of Genetics, Harvard Medical School, Boston, United States., Jang MY; Department of Genetics, Harvard Medical School, Boston, United States., Toepfer CN; Department of Genetics, Harvard Medical School, Boston, United States.; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.; Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom., Ward T; Department of Genetics, Harvard Medical School, Boston, United States., Kim Y; Department of Genetics, Harvard Medical School, Boston, United States., Pereira AC; Department of Genetics, Harvard Medical School, Boston, United States.; Laboratory of Genetics and Molecular Cardiology, Heart Institute, Medical School of University of Sao Paulo, Sao Paulo, Brazil., DePalma SR; Department of Genetics, Harvard Medical School, Boston, United States., Tai A; Department of Genetics, Harvard Medical School, Boston, United States., Kim S; Department of Genetics, Harvard Medical School, Boston, United States., Conner D; Department of Genetics, Harvard Medical School, Boston, United States., Bernstein D; Department of Pediatrics, Stanford University School of Medicine, Stanford, United States., Gelb BD; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States., Chung WK; Department of Medicine, Columbia University Medical Center, New York, United States., Goldmuntz E; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States., Porter G; Department of Pediatrics, University of Rochester Medical Center, Rochester, United States., Tristani-Firouzi M; Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, United States., Srivastava D; Gladstone Institutes, San Francisco, United States., Seidman JG; Department of Genetics, Harvard Medical School, Boston, United States., Seidman CE; Department of Genetics, Harvard Medical School, Boston, United States.; Howard Hughes Medical Institute, Harvard Medical School, Boston, United States.; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, United States.
مؤلفون مشاركون: Pediatric Cardiac Genomics Consortium
المصدر: ELife [Elife] 2020 Oct 15; Vol. 9. Date of Electronic Publication: 2020 Oct 15.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Diaphragm/*growth & development , GATA6 Transcription Factor/*genetics , Heart/*growth & development , Induced Pluripotent Stem Cells/*metabolism , Pancreas/*growth & development, Cell Differentiation/genetics ; Epigenesis, Genetic/genetics ; Gene Expression Profiling ; Humans ; Mutation, Missense/genetics ; Myocytes, Cardiac/metabolism
مستخلص: 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.
Competing Interests: AS, LW, JW, SM, JG, DD, MN, MS, RA, MJ, CT, TW, YK, AP, SD, AT, SK, DC, DB, BG, WC, EG, GP, MT, DS, JS, CS No competing interests declared
(© 2020, Sharma et al.)
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معلومات مُعتمدة: U01 HL098188 United States HL NHLBI NIH HHS; U01 HL098162 United States HL NHLBI NIH HHS; United States HHMI Howard Hughes Medical Institute; U01 HL098153 United States HL NHLBI NIH HHS; R01 HL080494 United States HL NHLBI NIH HHS; U01 HL153009 United States HL NHLBI NIH HHS; R01 HL057181 United States HL NHLBI NIH HHS; UM1 HL098166 United States HL NHLBI NIH HHS; UM1 HL128761 United States HL NHLBI NIH HHS; U01 HL098123 United States HL NHLBI NIH HHS; U01 HL098166 United States HL NHLBI NIH HHS; EEC-1647837 International National Science Foundation; U01 HL098163 United States HL NHLBI NIH HHS; T32 HL116273 United States HL NHLBI NIH HHS; United Kingdom WT_ Wellcome Trust; UM1 HL128711 United States HL NHLBI NIH HHS; U01 HL098147 United States HL NHLBI NIH HHS; UM1HL128711 United States NH NIH HHS
فهرسة مساهمة: Keywords: CRISPR; development; developmental biology; gene mutation; heart; human; iPSC; regenerative medicine; stem cells
سلسلة جزيئية: GEO GSM575227; GSM1151694; GSE51936; GSM575226
ClinicalTrials.gov NCT01196182
المشرفين على المادة: 0 (GATA6 Transcription Factor)
0 (GATA6 protein, human)
تواريخ الأحداث: Date Created: 20201015 Date Completed: 20210414 Latest Revision: 20210909
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC7593088
DOI: 10.7554/eLife.53278
PMID: 33054971
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.53278