Epigenetic landscape change analysis during human EMT sheds light on a key EMT mediator TRIM29

Abstract

Epithelial to mesenchymal transition (EMT) is a key trans-differentiation process, which plays a critical role in physiology and pathology. Although gene expression changes in EMT have been scrutinized, study of epigenome is in its infancy. To understand epigenetic changes during TWIST-driven EMT, we used the AcceSssIble assay to study DNA methylation and chromatin accessibility in human mammary epithelial cells (HMECs). The DNA methylation changes were found to have functional significance in EMT – i.e. methylated genes were enriched for E-box motifs that can be recognized by TWIST, at the promoters suggesting a potential targeting phenomenon, whereas the demethylated regions were enriched for pro-metastatic genes, supporting the role of EMT in metastasis. TWIST-induced EMT triggers alterations in chromatin accessibility both independent of and dependent on DNA methylation changes, primarily resulting in closed chromatin conformation. By overlapping the genes, whose chromatin structure is changed during early EMT and a known “core EMT signature”, we identified 18 driver candidate genes during EMT, 14 upregulated and 4 downregulated genes with corresponding chromatin structure changes. Among 18 genes, we focused on TRIM29 as a novel marker of EMT. Although loss of TRIM29 is insufficient to suppress CDH, it is enough to induce CDH2 and VIM. Gene functional annotation analysis shows the involvement of TRIM29 in epidermal development, cell differentiation and cell migration. Taken together, our results provide a robust snapshot of chromatin state during human EMT and identify TRIM29 as a core mediator of EMT.

RETRACTED ARTICLE: TRIM29 facilitates the epithelial-to-mesenchymal transition and the progression of colorectal cancer via the activation of the Wnt/β-catenin signaling pathway

“…Most experimental models require a dramatic change in the expression of epithelial and mesenchymal markers to confirm EMT: E-cadherin and occludins are the most commonly used markers for the epithelial trait and N-cadherin and vimentin for the mesenchymal trait [35, 36]. Recently, it has reported that the potential targets of TRIM29 are highly enriched in EMT-related cellular pathways, such as epidermal development, cellular differentiation, and cell junctions, suggesting that TRIM29 is a key mediator of EMT [37]. TRIM29 induced EMT and promoted migration and invasion in pancreatic and bladder cancer cells [19, 22].…”

Loss of TRIM29 Alters Keratin Distribution to Promote Cell Invasion in Squamous Cell Carcinoma

“…To date, TRIM29 has been reported to be positively or negatively involved in epithelial-mesenchymal transition (EMT) in cancers (10,36). RNAi-mediated gene knockdown of TRIM29 in breast cancer cell lines increases the expression of mesenchymal markers (N-cadherin and vimentin), decreases the expression of epithelial markers (E-cadherin), and increases the expression of the oncogenic transcriptional factor TWIST1, which is a key driver of EMT (10).…”

“…RNAi-mediated gene knockdown of TRIM29 in breast cancer cell lines increases the expression of mesenchymal markers (N-cadherin and vimentin), decreases the expression of epithelial markers (E-cadherin), and increases the expression of the oncogenic transcriptional factor TWIST1, which is a key driver of EMT (10). Another study used epigenetic change analysis to identify TRIM29 as a driver candidate during EMT (36). Furthermore, experimental model mice have revealed that TRIM29 facilitates EMT in pancreatic cancer cells (9).…”

Deregulation of Transcriptional Enhancers in Cancer

“…EMT is one of the main mechanisms fuelling the tumour plasticity and heterogeneity and entails dynamic changes in transcriptional and epigenetic landscapes ( Figure 1 ) [ 12 , 93 ]. Studying EMT in normal and transformed cells indicates dependency on global epigenetic reprograming, that starts with extracellular cytokine or the induction of EMT master regulators (e.g., TWIST and SNAIL ).…”