Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers

Cell Stem Cell. 2019 Jul 3;25(1):69-86.e5. doi: 10.1016/j.stem.2019.03.022. Epub 2019 May 9.


The cardiogenic transcription factors (TFs) Mef2c, Gata4, and Tbx5 can directly reprogram fibroblasts to induced cardiac-like myocytes (iCLMs), presenting a potential source of cells for cardiac repair. While activity of these TFs is enhanced by Hand2 and Akt1, their genomic targets and interactions during reprogramming are not well studied. We performed genome-wide analyses of cardiogenic TF binding and enhancer profiling during cardiac reprogramming. We found that these TFs synergistically activate enhancers highlighted by Mef2c binding sites and that Hand2 and Akt1 coordinately recruit other TFs to enhancer elements. Intriguingly, these enhancer landscapes collectively resemble patterns of enhancer activation during embryonic cardiogenesis. We further constructed a cardiac reprogramming gene regulatory network and found repression of EGFR signaling pathway genes. Consistently, chemical inhibition of EGFR signaling augmented reprogramming. Thus, by defining epigenetic landscapes these findings reveal synergistic transcriptional activation across a broad landscape of cardiac enhancers and key signaling pathways that govern iCLM reprogramming.

Keywords: Akt1; Gata4; Hand2; Mef2c; Tbx5; cardiomyocytes; direct reprogramming; heart regeneration; induced cardiac-like myocytes.

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
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cells, Cultured
  • Cellular Reprogramming
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Fibroblasts / physiology*
  • GATA4 Transcription Factor / genetics
  • Gene Regulatory Networks
  • Genome-Wide Association Study
  • MEF2 Transcription Factors / genetics
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / physiology*
  • Signal Transduction
  • T-Box Domain Proteins / genetics


  • Basic Helix-Loop-Helix Transcription Factors
  • GATA4 Transcription Factor
  • Hand2 protein, mouse
  • MEF2 Transcription Factors
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • EGFR protein, mouse
  • ErbB Receptors