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
  • 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: [email protected].
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.