miR-34 miRNAs provide a barrier for somatic cell reprogramming

Abstract

Somatic reprogramming efficiency by expression of defined transcription factors can be enhanced by deletion of p53. He and colleagues found that the microRNA miR-34, which is induced by p53 during reprogramming, inhibits reprogramming, partly by direct repression of pluripotency factors. Deletion of Mir34 from mice increases reprogramming efficiency and kinetics without affecting self-renewal and differentiation. Somatic reprogramming induced by defined transcription factors is a low-efficiency process that is enhanced by p53 deficiency1,2,3,4,5. So far, p21 is the only p53 target shown to contribute to p53 repression of iPSC (induced pluripotent stem cell) generation1,3, 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 of 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.