title: Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis.
abstract: Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Yen-Sin
authors.initials: YS
authors.lastname: Ang
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Renee N
authors.initials: RN
authors.lastname: Rivas
authors.affiliation: Department of Mechanical Engineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Alexandre J S
authors.initials: AJS
authors.lastname: Ribeiro
authors.affiliation: Department of Genetics and Center for Genomics and Personalized Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Rohith
authors.initials: R
authors.lastname: Srivas
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA.
authors.forename: Janell
authors.initials: J
authors.lastname: Rivera
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Stone
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA.
authors.forename: Karishma
authors.initials: K
authors.lastname: Pratt
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Tamer M A
authors.initials: TMA
authors.lastname: Mohamed
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA.
authors.forename: Ji-Dong
authors.initials: JD
authors.lastname: Fu
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA.
authors.forename: C Ian
authors.initials: CI
authors.lastname: Spencer
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Tippens
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA.
authors.forename: Molong
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Genetics and Center for Genomics and Personalized Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Narasimha
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Radzinsky
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Moon-Grady
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Mechanical Engineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pruitt
authors.affiliation: Department of Genetics and Center for Genomics and Personalized Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: dsrivastava@gladstone.ucsf.edu.
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D002843:Chromatin; D004742:Enhancer Elements, Genetic; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics*; D006321:Heart / Q000254:growth & development; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008297:Male; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics
chemical_list: D002843:Chromatin; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D019869:Phosphatidylinositol 3-Kinases
keywords: GATA4; TBX5; birth defect; cardiomyopathy; congenital heart defects; disease modeling; epigenetics; gene regulation; heart development; systems biology