ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner  

作　　者：Tian Chen Jian-Feng Xiang Shanshan Zhu Siye Chen Qing-Fei Yin Xiao-Ou Zhang Jun Zhang Hua Feng Rui Dong Xue-Jun Li Li Yang Ling-Ling Chen 

机构地区：[1]State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China [2]CAS Key Laboratory of Computational Biology, CAS Center for Excellence in Brain Science, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China [3]Department of Neuroscience, University of Connecticut Stem Cell Institute, University of Connecticut Health Center, Farmington, CT 06030, USA [4]School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China

出　　处：《Cell Research》2015年第4期459-476,共18页细胞研究（英文版）

基　　金：We are grateful to G Carmichael for critical reading of the manuscript, and all the lab members for helpful discussion. H9 cells were obtained from the WiCell Research Institute. This work was supported by the Ministry of Science and Technology of China （2014CB964802 and 2011CBA01105）, Chinese Academy of Sciences （XDA01010206）, the National Natural Science Foundation of China （91440202, 31271390, 31322018 and 31271376）.

摘　　要：Adenosine deaminases acting on RNA （ADARs） are involved in adenosine-to-inosine RNA editing and are implicated in development and diseases. Here we observed that ADAR1 deficiency in human embryonic stem cells （hESCs） significantly affected hESC differentiation and neural induction with widespread changes in mRNA and miRNA ex- pression, including upregulation of self-renewal-related miRNAs, such as miR302s. Global editing analyses revealed that ADAR1 editing activity contributes little to the altered miRNA/mRNA expression in ADARl-deficient hESCs upon neural induction. Genome-wide iCLIP studies identified that ADAR1 binds directly to pri-miRNAs to interfere with miRNA processing by acting as an RNA-binding protein. Importantly, aberrant expression of miRNAs and phe- notypes observed in ADARl-depleted hESCs upon neural differentiation could be reversed by an enzymatieally inactive ADAR1 mutant, but not by the RNA-binding-null ADAR1 mutant. These findings reveal that ADAR1, but not its editing activity, is critical for hESC differentiation and neural induction by regulating miRNA biogenesis via direct RNA interaction.

关 键 词：ADAR1 RNA editing embryonic stem cell neural induction MIRNA 

分 类 号：Q522[生物学—生物化学] Q42