2. Academic Validation
  3. Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis

Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis

  • Cell. 2016 Dec 15;167(7):1734-1749.e22. doi: 10.1016/j.cell.2016.11.033.
Yen-Sin Ang 1,  Renee N Rivas 1,  Alexandre J S Ribeiro 2,  Rohith Srivas 3,  Janell Rivera 4,  Nicole R Stone 1,  Karishma Pratt 4,  Tamer M A Mohamed 1,  Ji-Dong Fu 4,  C Ian Spencer 4,  Nathaniel D Tippens 5,  Molong Li 4,  Anil Narasimha 3,  Ethan Radzinsky 4,  Anita J Moon-Grady 6,  Haiyuan Yu 5,  Beth L Pruitt 2,  Michael P Snyder 3,  Deepak Srivastava 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Mechanical Engineering, Stanford University, Stanford, CA 94305, USA.
  • 3 Department of Genetics and Center for Genomics and Personalized Medicine, Stanford University, Stanford, CA 94305, USA.
  • 4 Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA.
  • 5 Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14850, USA.
  • 6 Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 7 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.
PMID: 27984724 DOI: 10.1016/j.cell.2016.11.033
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.

Keywords

GATA4; TBX5; birth defect; cardiomyopathy; congenital heart defects; disease modeling; epigenetics; gene regulation; heart development; systems biology.

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