Year: 2026
Type: preprint
Abstract: Epithelial-mesenchymal transition (EMT) is an essential process in development, tissue repair, and tumour metastasis, and is triggered by SNAI, ZEB and TWIST transcription factors, that recruit lysine-specific demethylase 1 (LSD1) to repress epithelial genes such as E-cadherin. In mesenchymal cells, LSD1 inhibition restores E-cadherin expression and reduces migration and invasion, consistent with LSD1 inhibition reverting EMT, and offering a therapeutic modality for EMT-associated disease. Recent data, however, suggest context-dependent roles for LSD1, as its inhibition in epithelial cells increases mesenchymal marker expression, potentially promoting EMT. To investigate this discrepancy, we mapped genome-wide binding of LSD1 in HCT116 epithelial cells and used rapid degron-mediated ablation of endogenous LSD1 to measure changes in nascent and steady-state transcription and chromatin accessibility. In epithelial cells, LSD1 binds constitutively-accessible, primed mesenchymal promoters. These are rapidly derepressed after LSD1 ablation, with activation of SNAI2 and ZEB1, which repress epithelial hallmarks such as E-cadherin. Re-introduction of LSD1 downregulates SNAI2 and ZEB1 but, surprisingly, further represses E-cadherin, indicating sustained loss of epithelial characteristics. Collectively, our results show that LSD1 maintains epithelial identity by repressing mesenchymal genes, questioning the therapeutic utility of LSD1 inhibition for EMT control.
Institutions: University of Leicester, University of Birmingham
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G3367711743, Understanding the diverse molecular mechanisms of chromatin-targeted histone deacetylase complexes, Understanding the unique properties of the Sin3A histone deacetylase complex in transcription and cell viability, Regulation of the transcription cycle by co-ordinate interaction of ATP-dependent chromatin remodelling and histone post-translational modifications., Understanding the diverse molecular mechanisms of chromatin-targeted histone deacetylase complexes, G5941218820, Imaging in vivo chromatin dynamics in Drosophila.
OpenAlex ID: W7225429559