Mnt represses epithelial identity to promote Epithelial to Mesenchymal Transition

The multi-step process of epithelial to mesenchymal transition (EMT), whereby static epithelial cells become migratory mesenchymal cells, plays a critical role during various developmental contexts, wound healing, and pathological conditions such as cancer metastasis. Despite the established function of basic helix-loop-helix (bHLH) transcription factors (TFs) in cell-fate determination, only a few have been examined for their role in EMT. Here, using transcriptome analysis of distinct stages during stepwise progression of TGFβ-induced EMT in mammary epithelial cells, we revealed distinct categories of bHLH TFs that show differential expression kinetics during EMT. Using a siRNA-mediated functional screen for bHLH TFs during EMT, we found Max network transcription repressor (MNT) to be essential for EMT in mammary epithelial cells. We show that the depletion of MNT blocks TGFβ-induced morphological changes during EMT, and this is accompanied by de-repression of a large number of epithelial genes. We show that MNT mediates the repression of epithelial identity genes during EMT by recruiting HDAC1 and mediating the loss of H3K27ac and chromatin accessibility. Lastly, we show that MNT is expressed at higher levels in EMT-High breast cancer cells and is required for their migration. Taken together, these findings establish MNT as a critical regulator of cell-fate changes during mammary EMT.