title: ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner.
abstract: 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 expression, 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 ADAR1-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 phenotypes observed in ADAR1-depleted hESCs upon neural differentiation could be reversed by an enzymatically 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.
authors.affiliation: 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.
authors.forename: Tian
authors.initials: T
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Xiang
authors.affiliation: 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.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Siye
authors.initials: S
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Qing-Fei
authors.initials: QF
authors.lastname: Yin
authors.affiliation: 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.
authors.forename: Xiao-Ou
authors.initials: XO
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Hua
authors.initials: H
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Dong
authors.affiliation: Department of Neuroscience, University of Connecticut Stem Cell Institute, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Li
authors.affiliation: 1] 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 [2] School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: 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] School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Chen
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D017393:RNA Editing / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016601:RNA-Binding Proteins; C000595356:ADAR protein, human; D000243:Adenosine Deaminase