Journal
NATURE CELL BIOLOGY
Volume 13, Issue 11, Pages 1353-U154Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2366
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Funding
- California Institute for Regenerative Medicine [RN2-00923-1]
- National Cancer Institute (NCI) [R01 CA139067, R00 CA126186]
- Siebel postdoctoral fellowship
- Directorate For Engineering [1015026] Funding Source: National Science Foundation
- Div Of Chem, Bioeng, Env, & Transp Sys [1015026] Funding Source: National Science Foundation
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Somatic reprogramming induced by defined transcription factors is a low-efficiency process that is enhanced by p53 deficiency(1-5). So far, p21 is the only p53 target shown to contribute to p53 repression of iPSC (induced pluripotent stem cell) generation(1,3), indicating that additional p53 targets may regulate this process. here, we demonstrate that miR-34 microRNAs (miRNAs), particularly miR-34a, exhibit p53-dependent induction during reprogramming. Mir34a deficiency in mice significantly increased reprogramming efficiency and kinetics, with miR-34a and p21 cooperatively regulating somatic reprogramming downstream of p53. Unlike p53 deficiency, which enhances reprogramming at the expense of iPSC pluripotency, genetic ablation for Mir34a promoted iPSC generation without compromising self-renewal or differentiation. Suppression of reprogramming by miR-34a was due, at least in part, to repression of pluripotency genes, including Nanog, Sox2 and Mycn (also known as N-Myc). This post-transcriptional gene repression by miR-34a also regulated iPSC differentiation kinetics. miR-34b and c similarly repressed reprogramming; and all three miR-34 miRNAs acted cooperatively in this process. taken together, our findings identified miR-34 miRNAs as p53 targets that play an essential role in restraining somatic reprogramming.
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