Grespi Francesca, Landré Vivien, Molchadsky Alina, Di Daniele Nicola, Marsella Luigi Tonino, Melino Gerry, Rotter Varda
Department of Biology, University of Padua, Padua, Italy.
Medical Research Council, Toxicology Unit, Leicester University, Hodgkin Building, Leicester, UK.
Cell Death Dis. 2016 Dec 29;7(12):e2567. doi: 10.1038/cddis.2016.419.
The tumour suppressor p53 plays an important role in somatic cell reprogramming. While wild-type p53 reduces reprogramming efficiency, mutant p53 exerts a gain of function activity that leads to increased reprogramming efficiency. Furthermore, induced pluripotent stem cells expressing mutant p53 lose their pluripotency in vivo and form malignant tumours when injected in mice. It is therefore of great interest to identify targets of p53 (wild type and mutant) that are responsible for this phenotype during reprogramming, as these could be exploited for therapeutic use, that is, formation of induced pluripotent stem cells with high reprogramming efficiency, but no oncogenic potential. Here we studied the transcriptional changes of microRNA in a series of mouse embryonic fibroblasts that have undergone transition to induced pluripotent stem cells with wild type, knock out or mutant p53 status in order to identify microRNAs whose expression during reprogramming is dependent on p53. We identified a number of microRNAs, with known functions in differentiation and carcinogenesis, the expression of which was dependent on the p53 status of the cells. Furthermore, we detected several uncharacterised microRNAs that were regulated differentially in the different p53 backgrounds, suggesting a novel role of these microRNAs in reprogramming and pluripotency.
肿瘤抑制因子p53在体细胞重编程中发挥着重要作用。野生型p53会降低重编程效率，而突变型p53则具有功能获得性活性，导致重编程效率提高。此外，表达突变型p53的诱导多能干细胞在体内会失去多能性，并在注射到小鼠体内时形成恶性肿瘤。因此，确定p53（野生型和突变型）在重编程过程中导致这种表型的靶点具有重要意义，因为这些靶点可用于治疗，即形成具有高重编程效率但无致癌潜力的诱导多能干细胞。在这里，我们研究了一系列小鼠胚胎成纤维细胞中微小RNA的转录变化，这些细胞已转变为具有野生型、敲除型或突变型p53状态的诱导多能干细胞，以便确定其在重编程过程中的表达依赖于p53的微小RNA。我们鉴定出了一些在分化和致癌过程中具有已知功能的微小RNA，其表达依赖于细胞的p53状态。此外，我们还检测到了几种在不同p53背景下差异调节的未表征微小RNA，这表明这些微小RNA在重编程和多能性方面具有新的作用。
