The lncRNA HOTAIR links the repressor Snail to epigenetic modifications of specific genomic sites in Epithelial-to-Mesenchymal Transition

The lncRNA HOTAIR links the repressor Snail to epigenetic modifications of specific genomic sites in Epithelial-to-Mesenchymal Transition Cecilia Battistelli 1,§, Carla Cicchini 1,§,, Laura Santangelo 1, Anna Tramontano 2, Marco Tripodi 1,3 1Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Rome, Italy 2Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Physics, Sapienza University of Rome, Rome, Italy 3National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy. §Co-first authors. Co-corresponding authors The transcription factor Snail is a master regulator of cellular identity and Epithelial-to-Mesenchymal Transition (EMT) directly repressing a broad repertoire of epithelial genes. How chromatin modifiers instrumental to its activity are recruited to Snail specific binding sites is unclear. Here we report that the long non-coding (lnc)RNA HOTAIR mediates a physical interaction between Snail and EZH2, enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2) and main writer of chromatin repressive marks. The Snail repressive activity, here monitored on genes with a pivotal function in epithelial and hepatic morphogenesis, differentiation and cell-type identity, depends on the formation of a tripartite Snail/HOTAIR/EZH2 complex. These results demonstrate a lncRNA-mediated mechanism by which a transcriptional factor conveys a general chromatin modifier to specific genes, thereby allowing the execution of hepatocyte transdifferentiation; moreover, they highlight HOTAIR as a crucial player in the Snail-mediated EMT.