ADAR1 is involved in the regulation of reprogramming human fibroblasts to induced pluripotent stem cells

Igal Germanguz, Ronit Shtrichman, Sivan Osenberg, Anna Ziskind, Atara Novak, Hagit Domev, Ilana Laevsky, Jasmine Jacob-Hirsch, Yulia Feiler, Gideon Rechavi, Joseph Itskovitz-Eldor

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)443-456
Number of pages14
JournalStem Cells and Development
Volume23
Issue number5
DOIs
StatePublished - 1 Mar 2014
Externally publishedYes

Funding

FundersFunder number
Flight Attendant Medical Research Institute

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