西班牙圣地亚哥大学(USC)健康研究所(IDIS)Miguel Fidalgo、Diana Guallar和美国哥伦比亚大学Jianlong Wang课题组合作取得新进展。他们发现ADAR1依赖性的RNA编辑可通过减弱内质网（ER）压力，促进间充质到上皮的转化（MET）和诱导多能干细胞（iPSC）重编程。这一研究成果发表在2020年5月11日的《细胞-干细胞》杂志上。

他们显示，在iPSC重编程过程中，ADAR1介导的腺苷到肌苷（A到I）编辑丢失会破坏MET。并阻碍诱导多能性的获得。使用化学和遗传方法，他们表明缺乏ADAR1依赖的RNA编辑通过双链RNA（dsRNA）传感器MDA5诱导畸形的先天免疫反应，释放ER压力并阻碍上皮命运的获得。

他们发现从A到I的编辑会阻止MDA5应答和螯合编码膜蛋白的dsRNA，这通过激活PERK依赖的未折叠蛋白应答途径，从而促进MET来促进ER稳态。因此，这项研究在细胞命运转变过程中为ADAR1及其A到I编辑活动确立了关键作用，并描绘了MET底层的关键调控层，以控制有效的重编程。

据介绍，A到I的RNA编辑被ADAR1催化，并大大改变了细胞的转录组，尽管在体细胞重编程中的功能性作用尚未得到充分研究。

附：英文原文

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

Author: 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 López, Carl R. Walkley, Jianlong Wang, Miguel Fidalgo

Issue&Volume: 2020-05-11

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 that A-to-I editing impedes MDA5 sensing and sequestration of dsRNAs encoding membrane proteins, which promote ER homeostasis by activating the PERK-dependent unfolded protein response pathway to consequently facilitate MET. This study therefore establishes a critical role for ADAR1 and its A-to-I editing activity during cell fate transitions and delineates a key regulatory layer underlying MET to control efficient reprogramming.

DOI: 10.1016/j.stem.2020.04.016

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30155-7