miR-200 represses primary ciliogenesis by direct repression of DZIP1

The miR-200 family enforces epithelial identity through suppression of transcriptional and signalling networks that promote Epithelial-Mesenchymal Transition (EMT). Defining features of EMT include cytoskeletal remodelling, altered cell-surface protein expression that reconfigures cell–cell and cell–matrix interactions, and the promotion of primary cilia; specialized membrane protrusions that concentrate receptors and signal transduction proteins to function as antennae for extracellular cues. Such cilia promote stemness and chemoresistance, however the mechanism underlying their upregulation has remained unclear. Here, we identify a previously unrecognised role for miR-200c in controlling ciliogenesis through direct repression of DZIP1, a conserved ciliogenesis assembly factor. miR-200c-mediated repression of DZIP1 is necessary and sufficient to inhibit cilia formation, as DZIP1 knockdown phenocopies miR-200 in reducing ciliation, while DZIP1 re-expression rescues cilia loss. While DZIP1 perturbation alone does not alter canonical EMT markers or the ability of miR-200 to drive MET, transcriptomic profiling shows that a subset of miR-200-responsive gene expression changes are DZIP1-dependent, indicating that miR-200 modulates cilia-associated signalling networks. These findings extend the functional repertoire of miR-200 to include the ciliary sensory structures themselves, as well as co-targeting downstream cytoskeletal and signalling network components. We propose that by suppressing ciliation, sensitivity to pro-EMT stimuli is dampened and epithelial cells are buffered against inappropriate EMT activation.