HOTAIR requires epitranscriptomic modification to exert its pivotal epigenetic role in Epithelial to Mesenchymal Transition

While m6A epitranscriptomic modification has been shown to impact several mRNAs maturation, stability/degradation, nuclear/ cytoplasm export and translation regulation, its impact on lncRNAs activity is yet largely uncharacterized. Here, we show that the silencing of the m6A writer METTL3 inhibits Epithelial to Mesenchymal Transition (EMT), morphological, migratory and invasive features of TGFβ-treated epithelial cells as well as of tumor cells. Building on previous evidence pinpointing the lncHOTAIR as a mandatory element for epithelial genes’ repression triggering EMT, here we uncover a dominant role of an epitranscriptomic modification on the epigenetic function of this lncRNA. Mechanistically, HOTAIR is m6A-modified on the interaction domains with both the master transcriptional factor of EMT SNAIL and the general chromatin modifier EZH2. This epitranscriptomic modification is necessary for the interaction between HOTAIR and SNAIL/EZH2 and in turn for HOTAIR-dependent epigenetic repression on SNAIL-targeted epithelial genes. Impairing m6A modification impedes the assembling of the tripartite SNAIL/HOTAIR/EZH2 complex and in turn blocks EMT accomplishment. Overall, we unveil that the epitranscriptomic modification m6A has a dominant role on the epigenetic function of a lncRNA.