RNA chemical modifications are intricately linked to transcriptome structural and functional diversity. Whereas somatic cell reprogramming involves a profound rewiring of epigenetic and transcriptomic landscapes, how RNA modifications contribute to overriding somatic cell identity is incompletely understood. Here we demonstrate that loss of Adenosine-to-Inosine (A-to-I) editing of RNA by ADAR1 hampers mesenchymal-to-epithelial transition (MET) and impedes induced pluripotent stem cell (iPSC) formation. Absence of RNA editing leads to aberrant innate immune response (IIR) expression programs, which unleash endoplasmic reticulum (ER) stress and hinder epithelial fate acquisition. Using chemical and genetic approaches, we show a dual role for A-to-I editing in preventing MDA5-dependent activation of ER stress and ensuring proper double strand RNA (dsRNA) compartmentalization for PERK activation. Thus, our study establishes a critical role for A-to-I RNA modification in cell fate transitions during reprogramming, which delineates a novel regulatory layer underlying MET control for efficient reprogramming.
Guallar, Diana and Fuentes-Iglesias, Alejandro and Souto, Yara and Freire-Agulleiro, Oscar and Pardavila, Jose Angel and Saenz, Carmen and Escudero, Adriana and Ameneiro, Cristina and Garcia-Outeiral, Vera and Xiong, Heng and Moreira, Tiago and Liu, Dongbing and Xiao, Shidi and Hou, Yong and Wu, Kui and Hartner, Jochen C. and Blanco, Miguel G. and Lee, Leo J. and López, Miguel and Walkley, Carl R. and Wang, Jianlong and Fidalgo, Miguel, ADAR1 Safeguards MET by Suppressing ER Stress Through RNA Editing in Promoting Reprogramming (August 29, 2019). Available at SSRN: https://ssrn.com/abstract=3444607 or http://dx.doi.org/10.2139/ssrn.3444607
This version of the paper has not been formally peer reviewed.
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