A lncRNA-mediated interaction between Snail and Ezh2 governs epigenetic modifications causal to EMT of the hepatocyte

A lncRNA-mediated interaction between Snail and Ezh2 governs epigenetic modifications causal to EMT of the hepatocyte Cecilia Battistelli1, Carla Cicchini1, Laura Santangelo1, Anna Tramontano2, Laura Amicone1 and Marco Tripodi1 1Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Rome, Italy 2Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physics, Sapienza University of Rome, Rome, Italy Co-authors Epithelial-to-Mesenchymal Transition (EMT) and the reverse Mesenchymal-to-Epithelial Transition (MET) are manifestations of cellular plasticity that imply a dynamic and profound gene expression reprogramming. We previously demonstrated that the balance between two transcriptional factors, Snail (EMT “master factor) and HNF4α (MET “master” factor), able to reciprocally repress their own expression, ultimately influences the outcome of the transition between the mesenchymal/ undifferentiated and the epithelial/differentiated phenotype. This necessarily implies that these master factors act in a much more complex macromolecular systems, able to direct and modulate a whole transcriptional profile. Starting from the working hypothesis that a transcriptional factor sufficient to trigger and drive EMT might be endowed with the capacity to locally impact chromatin modifications causal to its repressive role, we investigated on how chromatin modifiers instrumental to Snail repressive activity are recruited to its specific sites. We found that a long non-coding RNA mediates a physical interaction between Snail and EZH2, enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2) and the main writer of chromatin repressive marks and demonstrated that a tripartite Snail/lncRNA/EZH2 complex is causal for the execution of a full EMT of hepatocytes. 2006-Cicchini C, et al. J Cell Physiol. Oct; 209(1):230-8. 2011- Santangelo L, et al. Hepatology Jun;53(6):2063-74 2012-Garibaldi F, et al Cell Death and Differentiation. Jun;19(6):937-46. 2015-Cicchini C, et al. Liver Int. Apr 25. doi: 10.1111/liv.12577. 2015-Cicchini C, et al. BBA GRM Volume 1849, Issue 8, August, Pages 919–929.