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.

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.

MeSH terms

  • Chromatin
  • Enhancer Elements, Genetic
  • Female
  • GATA4 Transcription Factor / genetics*
  • Heart / growth & development
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / pathology*
  • Humans
  • Induced Pluripotent Stem Cells
  • Male
  • Mutation, Missense
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Signal Transduction
  • T-Box Domain Proteins / genetics

Substances

  • Chromatin
  • GATA4 Transcription Factor
  • GATA4 protein, human
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Phosphatidylinositol 3-Kinases