Transforming growth factor-β1 induces super-enhancers at the loci of the epithelial-mesenchymal transition-related genes in human keratinocyte HaCaT cells

An enhancer is a genomic DNA sequence that substantially enhances the transcriptional activity of a target gene by recruiting transcription factors. The large clusters of enhancers identified through the ChIP-seq analysis of histone H3 lysine 27 acetylation (H3K27ac) are called super-enhancers (SEs). This study examined the dynamics of SEs during transforming growth factor (TGF)-β1-mediated epithelial-mesenchymal transition (EMT) in the human keratinocyte cell line HaCaT. Initially, we identified the constitutive and the TGF-β1 signal-dependent SE regions across the HaCaT genome. The TGF-β1-induced SEs were detected at the loci of genes associated with the cell cycle, cell death, and extracellular matrix organization. Notably, the EMT-related mesenchymal genes such as FN1 and SERPINE1 gained the SEs on their loci in response to TGF-β1. Next, we investigated the functional role of BRD4, a transcriptional mediator that binds to the SEs, in the expression of TGF-β1-induced SE-associated genes. JQ-1, a potent inhibitor of BRD4, effectively reduced the TGF-β1-induced mRNA expression of FN1 and SERPINE1. In conclusion, this study demonstrated that the rearrangement of SEs is crucial for the transcriptional regulation of the TGF-β1-induced EMT in HaCaT cells.