ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress

In contrast to chromatin and DNA modifications, whose roles has been widely investigated, the contribution of RNA epitranscriptomics to specification of cellular identity remains largely unexplored. In this study we demonstrated that loss-of-function of ADAR1, an enzyme that catalyzes adenosine deamination in RNA, abrogates epithelial cell fate acquisition during somatic cell reprogramming. Our findings indicate that absence of A-to-I editing triggers innate immune response and endoplasmic reticulum stress by the cytoplasmic sensor MDA5, resulting in reduced Mesenchymal-to-Epithelial Transition (MET). Additionally, ADAR1 catalytic activity regulates the subcellular distribution of double-strand containing RNAs encoding protein-related membranes. Our study uncovers for the first time the implication of A-to-I RNA editing in cellular plasticity and epithelial specification. RNA profiling at day 7 of somatic cell reprogramming in Adar Fl/E861A+Veh, AdarFl/E861+4OHT, Adar Fl/Fl +Veh and Adar Fl/Fl+4OHT Mouse Embryonic Fibroblasts.