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Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.

ABSTRACT: Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151?kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.

SUBMITTER: Yang B

PROVIDER: S-EPMC5458508 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.

Yang Bo B Zhou Wei W Jiao Jiao J Nielsen Jonas B JB Mathis Michael R MR Heydarpour Mahyar M Lettre Guillaume G Folkersen Lasse L Prakash Siddharth S Schurmann Claudia C Fritsche Lars L Farnum Gregory A GA Lin Maoxuan M Othman Mohammad M Hornsby Whitney W Driscoll Anisa A Levasseur Alexandra A Thomas Marc M Farhat Linda L Dubé Marie-Pierre MP Isselbacher Eric M EM Franco-Cereceda Anders A Guo Dong-Chuan DC Bottinger Erwin P EP Deeb G Michael GM Booher Anna A Kheterpal Sachin S Chen Y Eugene YE Kang Hyun Min HM Kitzman Jacob J Cordell Heather J HJ Keavney Bernard D BD Goodship Judith A JA Ganesh Santhi K SK Abecasis Gonçalo G Eagle Kim A KA Boyle Alan P AP Loos Ruth J F RJF Eriksson Per P Tardif Jean-Claude JC Brummett Chad M CM Milewicz Dianna M DM Body Simon C SC Willer Cristen J CJ

Nature communications 20170525

Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted b ...[more]

PMID: 28541271

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Project description:BackgroundThe endothelial-mesenchymal transition (EndoMT) is a fundamental process for heart valve formation and defects in EndoMT cause aortic valve abnormalities. Our previous genome-wide association study identified multiple variants in a large chromosome 8 segment as significantly associated with bicuspid aortic valve (BAV). The objective of this study is to determine the biological effects of this large noncoding segment in human induced pluripotent stem cell (hiPSC)-based EndoMT.MethodsA large genomic segment enriched for BAV-associated variants was deleted in hiPSCs using 2-step CRISPR/Cas9 editing. To address the effects of the variants on GATA4 expression, we generated CRISPR repression hiPSC lines (CRISPRi) as well as hiPSCs from BAV patients. The resulting hiPSCs were differentiated to mesenchymal/myofibroblast-like cells through cardiovascular-lineage endothelial cells for molecular and cellular analysis. Single-cell RNA sequencing was also performed at different stages of EndoMT induction.ResultsThe large deletion impaired hiPSC-based EndoMT in multiple biallelic clones compared with their isogenic control. It also reduced GATA4 transcript and protein levels during EndoMT, sparing the other genes nearby the deletion segment. Single-cell trajectory analysis revealed the molecular reprogramming during EndoMT. Putative GATA-binding protein targets during EndoMT were uncovered, including genes implicated in endocardial cushion formation and EndoMT process. Differentiation of cells derived from BAV patients carrying the rs117430032 variant as well as CRISPRi repression of the rs117430032 locus resulted in lower GATA4 expression in a stage-specific manner. TWIST1 was identified as a potential regulator of GATA4 expression, showing specificity to the locus tagged by rs117430032.ConclusionsBAV-associated distal regions regulate GATA4 expression during hiPSC-based EndoMT, which in turn promotes EndoMT progression, implicating its contribution to heart valve development.

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Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.

Publications

Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.

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