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Enhancer Reprogramming within Pre-existing Topologically Associated Domains Promotes TGF-β-Induced EMT and Cancer Metastasis
- Source :
- Mol Ther
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Transcriptional Activation
Epithelial-Mesenchymal Transition
Carcinogenesis
Muscle Proteins
Histone Deacetylase 1
Smad2 Protein
Histones
03 medical and health sciences
Histone H3
Mice
0302 clinical medicine
Transforming Growth Factor beta
Drug Discovery
Genetics
Animals
Humans
TEAD4
Epithelial–mesenchymal transition
Smad3 Protein
Neoplasm Metastasis
Enhancer
Molecular Biology
030304 developmental biology
Epigenomics
Pharmacology
Regulation of gene expression
0303 health sciences
biology
Chemistry
TEA Domain Transcription Factors
Cellular Reprogramming
Cell biology
DNA-Binding Proteins
Histone
Enhancer Elements, Genetic
HEK293 Cells
A549 Cells
030220 oncology & carcinogenesis
biology.protein
Hepatocyte Nuclear Factor 3-beta
Hepatocytes
Molecular Medicine
Original Article
Reprogramming
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 15250024
- Volume :
- 28
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Accession number :
- edsair.doi.dedup.....ff9617fcb00924d2af4954dda85da8a0