Journal article

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

Diana Guallar, Alejandro Fuentes-Iglesias, Yara Souto, Cristina Ameneiro, Oscar Freire-Agulleiro, Jose Angel Pardavila, Adriana Escudero, Vera Garcia-Outeiral, Tiago Moreira, Carmen Saenz, Heng Xiong, Dongbing Liu, Shidi Xiao, Yong Hou, Kui Wu, Daniel Torrecilla, Jochen C Hartner, Miguel G Blanco, Leo J Lee, Miguel Lopez Show all

CELL STEM CELL | CELL PRESS | Published : 2020

Abstract

RNA editing of adenosine to inosine (A to I) is catalyzed by ADAR1 and dramatically alters the cellular transcriptome, although its functional roles in somatic cell reprogramming are largely unexplored. Here, we show that loss of ADAR1-mediated A-to-I editing disrupts mesenchymal-to-epithelial transition (MET) during induced pluripotent stem cell (iPSC) reprogramming and impedes acquisition of induced pluripotency. Using chemical and genetic approaches, we show that absence of ADAR1-dependent RNA editing induces aberrant innate immune responses through the double-stranded RNA (dsRNA) sensor MDA5, unleashing endoplasmic reticulum (ER) stress and hindering epithelial fate acquisition. We found..

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Grants

Awarded by FEDER Program of the EU


Awarded by Xunta de GaliciaConselleria de Cultura, Educacion e Ordenacion Universitaria


Awarded by Fundacion Ramon Areces


Awarded by New York State Department of Health


Awarded by National Institutes of Health (NIH)


Awarded by National Health and Medical Research Council (NHMRC)


Awarded by Australian Research Council


Awarded by Victorian Cancer Agency research fellowship


Awarded by Xunta de Galicia


Awarded by Ministerio de Economi'a y Competitividad (MINECO) - FEDER Program of the EU


Awarded by Atresmedia - Guangzhou Health-Medical Collaborative Innovation Project


Awarded by Ramon y Cajal awards


Awarded by Weill-Caulier Trusts Career Scientist Award


Awarded by Ministerio de Ciencia, Innovacion y Universidades


Funding Acknowledgements

We thank M. Jantsch for the A-to-I RNA editing reporter constructs and M. Wernig (Ascl1) and D. Pei (7F cocktail) for overexpressing constructs. This research was funded by grants from the Spanish Agencia Estatal de Investigacion, co-funded by the FEDER Program of the EU (BFU2016-80899-P to M.F. and RTI2018-096708-J-I00 to D.G.) (AEI/FEDER, UE); the Xunta de GaliciaConselleria de Cultura, Educacion e Ordenacion Universitaria (ED431F 2016/016 to M.F.); the Fundacion Ramon Areces (2016-PO025 to M.F.); the New York State Department of Health (C32583GG and C32569GG to J.W.); and the National Institutes of Health (NIH) (GM129157, HD095938, and HD097268 to J.W.). Research from the C.R.W. laboratory was supported by the National Health and Medical Research Council (NHMRC) (APP1102006/APP1144049), the Australian Research Council (DP180103989), and a Victorian Cancer Agency research fellowship (MCRF15015). Research from the M.L. laboratory was supported by Xunta de Galicia (2016-PG068) and Ministerio de Economi ' a y Competitividad (MINECO), co-funded by the FEDER Program of the EU (RTI2018-101840-B-I00) and Atresmedia. L.J.L. was funded by the Guangzhou Health-Medical Collaborative Innovation Project (201400000004-5). M.F. and M.G.B. are recipients of Ramon y Cajal awards (RYC-2014-16779 to M.F. and RYC-2012-10835 to M.G.B.) from the MINECO of Spain, and J.W. is a recipient of an Irma T. Hirschl and Weill-Caulier Trusts Career Scientist Award. A.F.-I. (MINECO, BES-2017-082007), Y.S. (Xunta de Galicia, ED481A-2017/166), and A.E. and V.G.-O. (Ministerio de Ciencia, Innovacion y Universidades, FPU2018/01246 and FPU17/01131, respectively) are recipients of fellowships. CIBER de Fisiopatologia de la Obesidad y Nutricion is an initiative of ISCIII.