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

  • Author(s): Ang, Yen-Sin
  • Rivas, Renee N
  • Ribeiro, Alexandre JS
  • Srivas, Rohith
  • Rivera, Janell
  • Stone, Nicole R
  • Pratt, Karishma
  • Mohamed, Tamer MA
  • Fu, Ji-Dong
  • Spencer, C Ian
  • Tippens, Nathaniel D
  • Li, Molong
  • Narasimha, Anil
  • Radzinsky, Ethan
  • Moon-Grady, Anita J
  • Yu, Haiyuan
  • Pruitt, Beth L
  • Snyder, Michael P
  • Srivastava, Deepak
  • et al.

Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5180611/
No data is associated with this publication.
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.

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