title: Alu sequences in undifferentiated human embryonic stem cells display high levels of A-to-I RNA editing.
abstract: Adenosine to Inosine (A-to-I) RNA editing is a site-specific modification of RNA transcripts, catalyzed by members of the ADAR (Adenosine Deaminase Acting on RNA) protein family. RNA editing occurs in human RNA in thousands of different sites. Some of the sites are located in protein-coding regions but the majority is found in non-coding regions, such as 3'UTRs, 5'UTRs and introns - mainly in Alu elements. While editing is found in all tissues, the highest levels of editing are found in the brain. It was shown that editing levels within protein-coding regions are increased during embryogenesis and after birth and that RNA editing is crucial for organism viability as well as for normal development. In this study we characterized the A-to-I RNA editing phenomenon during neuronal and spontaneous differentiation of human embryonic stem cells (hESCs). We identified high editing levels of Alu repetitive elements in hESCs and demonstrated a global decrease in editing levels of non-coding Alu sites when hESCs are differentiating, particularly into the neural lineage. Using RNA interference, we showed that the elevated editing levels of Alu elements in undifferentiated hESCs are highly dependent on ADAR1. DNA microarray analysis showed that ADAR1 knockdown has a global effect on gene expression in hESCs and leads to a significant increase in RNA expression levels of genes involved in differentiation and development processes, including neurogenesis. Taken together, we speculate that A-to-I editing of Alu sequences plays a role in the regulation of hESC early differentiation decisions.
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Sivan
authors.initials: S
authors.lastname: Osenberg
authors.forename: Nurit
authors.initials: N
authors.lastname: Paz Yaacov
authors.forename: Michal
authors.initials: M
authors.lastname: Safran
authors.forename: Sharon
authors.initials: S
authors.lastname: Moshkovitz
authors.forename: Ronit
authors.initials: R
authors.lastname: Shtrichman
authors.forename: Ofra
authors.initials: O
authors.lastname: Sherf
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Gilmor
authors.initials: G
authors.lastname: Keshet
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Joseph
authors.initials: J
authors.lastname: Itskovitz-Eldor
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020087:Alu Elements / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D007288:Inosine / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology; D016366:Open Reading Frames / Q000235:genetics; D017393:RNA Editing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D007288:Inosine; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D000241:Adenosine