title: ADAR1 is involved in the regulation of reprogramming human fibroblasts to induced pluripotent stem cells.
abstract: Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional, site-specific modification process that is catalyzed by Adenosine Deaminase Acting on RNA (ADAR) gene family members. Since ADARs act on double-stranded RNA, most A-to-I editing occurs within repetitive elements, particularly Alu elements, as the result of the inherent property of these sequences to fold and form double strands. ADAR1-mediated A-to-I RNA editing was recently implicated in the regulation of human embryonic stem cells (hESCs). Spontaneous and neuronal differentiation of hESC was shown to result in a decrease in A-to-I editing levels. Knockdown of ADAR1 in hESCs results in an elevation of the expression of differentiation-related genes. In addition, we found that hESCs over-expressing ADAR1 could not be generated. The current study shows that the editing levels of induced pluripotent stem cells (iPSCs) change throughout reprogramming, from a source cell level to a level similar to that of hESCs. Up- or down-regulation of the ADAR1 level in human foreskin fibroblast (HFF) cells before induction of reprogramming results in varied reprogramming efficiencies. Furthermore, HFF-iPSC early clones derived from source cells in which the ADAR1 level was down-regulated lose their iPSC properties shortly after iPSC colony formation and instead exhibit characteristics of cancer cells. Taken together, our results imply a role for ADAR1 in the regulation of pluripotency induction as well as in the maintenance of early iPSC properties.
authors.affiliation: 1 Ruth and Bruce Rappaport Faculty of Medicine, Sohnis and Forman Families Center for Stem Cell and Tissue Regeneration Research , Technion, Haifa, Israel .
authors.forename: Igal
authors.initials: I
authors.lastname: Germanguz
authors.forename: Ronit
authors.initials: R
authors.lastname: Shtrichman
authors.forename: Sivan
authors.initials: S
authors.lastname: Osenberg
authors.forename: Anna
authors.initials: A
authors.lastname: Ziskind
authors.forename: Atara
authors.initials: A
authors.lastname: Novak
authors.forename: Hagit
authors.initials: H
authors.lastname: Domev
authors.forename: Ilana
authors.initials: I
authors.lastname: Laevsky
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Yulia
authors.initials: Y
authors.lastname: Feiler
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Joseph
authors.initials: J
authors.lastname: Itskovitz-Eldor
mesh_terms: D000243:Adenosine Deaminase / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D053595:Embryonic Stem Cells; D005347:Fibroblasts; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D016601:RNA-Binding Proteins
chemical_list: D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase