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ADAR1 Safeguards MET by Suppressing ER Stress Through RNA Editing in Promoting Reprogramming

75 Pages Posted: 3 Sep 2019 Sneak Peek Status: Review Complete

See all articles by Diana Guallar

Diana Guallar

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Alejandro Fuentes-Iglesias

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Yara Souto

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Oscar Freire-Agulleiro

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Jose Angel Pardavila

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Carmen Saenz

Mount Sinai Health System - Black Family Stem Cell Institute

Adriana Escudero

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Cristina Ameneiro

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Vera Garcia-Outeiral

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Heng Xiong

Beijing Genomics Institute (BGI)

Tiago Moreira

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Dongbing Liu

Beijing Genomics Institute (BGI)

Shidi Xiao

Beijing Genomics Institute (BGI)

Yong Hou

Beijing Genomics Institute (BGI)

Kui Wu

Beijing Genomics Institute (BGI)

Jochen C. Hartner

Taconic Biosciences

Miguel G. Blanco

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Leo J. Lee

Beijing Genomics Institute (BGI)

Miguel López

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Carl R. Walkley

University of Melbourne

Jianlong Wang

Mount Sinai Health System - Black Family Stem Cell Institute

Miguel Fidalgo

Universidade de Santiago de Compostela - Departamento de Fisioloxía

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Abstract

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.

Keywords: RNA A-to-I editing, ADAR1, somatic cell reprogramming, iPSC, pluripotency, MET, ER stress, UPR, innate immune response, Subcellular Localization

Suggested Citation

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). CELL-STEM-CELL-D-19-00583. Available at SSRN: https://ssrn.com/abstract=3444607 or http://dx.doi.org/10.2139/ssrn.3444607
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Diana Guallar

Universidade de Santiago de Compostela - Departamento de Fisioloxía ( email )

15782
Santiago de Compostela
Spain

Alejandro Fuentes-Iglesias

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Yara Souto

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Oscar Freire-Agulleiro

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Jose Angel Pardavila

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Carmen Saenz

Mount Sinai Health System - Black Family Stem Cell Institute

One Gustave L. Levy Place
New York, NY 10029-6574
United States

Adriana Escudero

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Cristina Ameneiro

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Vera Garcia-Outeiral

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Heng Xiong

Beijing Genomics Institute (BGI)

Shenzhen, Guangdong 518083
China

Tiago Moreira

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Dongbing Liu

Beijing Genomics Institute (BGI)

Shenzhen, Guangdong 518083
China

Shidi Xiao

Beijing Genomics Institute (BGI)

Shenzhen, Guangdong 518083
China

Yong Hou

Beijing Genomics Institute (BGI) ( email )

Shenzhen, Guangdong 518083
China

Kui Wu

Beijing Genomics Institute (BGI)

Shenzhen, Guangdong 518083
China

Jochen C. Hartner

Taconic Biosciences

United Kingdom

Miguel G. Blanco

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Leo J. Lee

Beijing Genomics Institute (BGI)

Shenzhen, Guangdong 518083
China

Miguel López

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Carl R. Walkley

University of Melbourne

185 Pelham Street
Carlton, Victoria 3053
Australia

Jianlong Wang

Mount Sinai Health System - Black Family Stem Cell Institute ( email )

One Gustave L. Levy Place
New York, NY 10029-6574
United States

Miguel Fidalgo (Contact Author)

Universidade de Santiago de Compostela - Departamento de Fisioloxía ( email )

15782
Santiago de Compostela
Spain

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