Enhancer Reprogramming within Pre-existing Topologically Associated Domains Promotes TGF-β-Induced EMT and Cancer Metastasis

Mol Ther. 2020 Sep 2;28(9):2083-2095. doi: 10.1016/j.ymthe.2020.05.026. Epub 2020 Jun 1.


Transcription growth factor β (TGF-β) signaling-triggered epithelial-to-mesenchymal transition (EMT) process is associated with tumor stemness, metastasis, and chemotherapy resistance. However, the epigenomic basis for TGF-β-induced EMT remains largely unknown. Here we reveal that HDAC1-mediated global histone deacetylation and the gain of specific histone H3 lysine 27 acetylation (H3K27ac)-marked enhancers are essential for the TGF-β-induced EMT process. Enhancers gained upon TGF-β treatment are linked to gene activation of EMT markers and cancer metastasis. Notably, dynamic enhancer gain or loss mainly occurs within pre-existing topologically associated domains (TADs) in epithelial cells, with minimal three-dimensional (3D) genome architecture reorganization. Through motif enrichment analysis of enhancers that are lost or gained upon TGF-β stimulation, we identify FOXA2 as a key factor to activate epithelial-specific enhancer activity, and we also find that TEAD4 forms a complex with SMAD2/3 to mediate TGF-β signaling-triggered mesenchymal enhancer reprogramming. Together, our results implicate that key transcription-factor (TF)-mediated enhancer reprogramming modulates the developmental transition in TGF-β signaling-associated cancer metastasis.

Keywords: EMT; FOXA2; Hi-C; TEAD2; TEAD4; TGFβ; enhancer reprogramming; epithelial-to-mesenchymal transition; metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Cellular Reprogramming / drug effects*
  • DNA-Binding Proteins / metabolism
  • Enhancer Elements, Genetic / drug effects*
  • Epithelial-Mesenchymal Transition / drug effects*
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Hepatocytes / metabolism
  • Histone Deacetylase 1 / metabolism
  • Histones / metabolism
  • Humans
  • Mice
  • Muscle Proteins / metabolism
  • Neoplasm Metastasis
  • Signal Transduction / drug effects*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • TEA Domain Transcription Factors
  • Transcription Factors / metabolism
  • Transcriptional Activation / drug effects
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology*


  • DNA-Binding Proteins
  • FOXA2 protein, human
  • Histones
  • Muscle Proteins
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • TEA Domain Transcription Factors
  • TEAD4 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta
  • Hepatocyte Nuclear Factor 3-beta
  • HDAC1 protein, human
  • Histone Deacetylase 1