Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming

Cell Stem Cell. 2019 Jul 3;25(1):87-102.e9. doi: 10.1016/j.stem.2019.06.012.


Ectopic expression of combinations of transcription factors (TFs) can drive direct lineage conversion, thereby reprogramming a somatic cell's identity. To determine the molecular mechanisms by which Gata4, Mef2c, and Tbx5 (GMT) induce conversion from a cardiac fibroblast toward an induced cardiomyocyte, we performed comprehensive transcriptomic, DNA-occupancy, and epigenomic interrogation throughout the reprogramming process. Integration of these datasets identified new TFs involved in cardiac reprogramming and revealed context-specific roles for GMT, including the ability of Mef2c and Tbx5 to independently promote chromatin remodeling at previously inaccessible sites. We also find evidence for cooperative facilitation and refinement of each TF's binding profile in a combinatorial setting. A reporter assay employing newly defined regulatory elements confirmed that binding of a single TF can be sufficient for gene activation, suggesting that co-binding events do not necessarily reflect synergy. These results shed light on fundamental mechanisms by which combinations of TFs direct lineage conversion.

Keywords: ATAC-seq; ChIP-seq; cardiac fibroblast; cardiomyocyte; reprogramming; single-cell RNA-seq; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Lineage
  • Cells, Cultured
  • Cellular Reprogramming
  • Chromatin Assembly and Disassembly
  • Epigenesis, Genetic
  • GATA4 Transcription Factor / genetics
  • GATA4 Transcription Factor / metabolism*
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism*
  • Machine Learning
  • Mice
  • Myocytes, Cardiac / physiology*
  • Protein Binding
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • Transcriptional Activation


  • GATA4 Transcription Factor
  • Gata4 protein, mouse
  • MEF2 Transcription Factors
  • T-Box Domain Proteins
  • T-box transcription factor 5