The oncogene c-Jun impedes somatic cell reprogramming
The oncogene c-Jun impedes somatic cell reprogramming
复制标题
癌基因 c-Jun 阻碍体细胞重编程。
DOI：
10.1038/ncb3193
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发表时间：
2015-07-01
影响因子：
21.3
通讯作者：
Pei, Duanqing
中科院分区：
文献类型：
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作者：
Liu, Jing;Han, Qingkai;Pei, Duanqing
已知致癌转录因子可介导体细胞向肿瘤或诱导多能干细胞 (iPSC) 的转化。在这里，我们报告 c-Jun 作为 iPSC 形成的障碍。 c-Jun 由小鼠胚胎成纤维细胞 (MEF) 表达，并且是其增殖所必需的，但小鼠胚胎干细胞 (mESC) 不表达 c-Jun。一致地，c-Jun 在 mESC 分化过程中被诱导，驱动 mESC 向内胚层谱系发展，并完全阻止 MEF 生成 iPSC。从机制上讲，c-Jun 激活间充质相关基因，广泛抑制多能基因，并在重编程过程中破坏必要的间充质到上皮的转变。此外，shRNA、显性失活 c-Jun 或 Jdp2 对 c-Jun 的抑制增强了重编程并取代了山中因子中的 Oct4。最后，Jdp2 锚定 5 个非 Yamanaka 因子（Id1、Jhdm1b、Lrh1、Sall4 和 Glis1），将 MEF 重编程为 iPSC。我们的研究表明 c-Jun 是体细胞命运的守护者，它的抑制打开了多能性之门。
Oncogenic transcription factors are known to mediate the conversion of somatic cells to tumour or induced pluripotent stem cells (iPSCs). Here we report c-Jun as a barrier for iPSC formation. c-Jun is expressed by and required for the proliferation of mouse embryonic fibroblasts (MEFs), but not mouse embryonic stem cells (mESCs). Consistently, c-Jun is induced during mESC differentiation, drives mESCs towards the endoderm lineage and completely blocks the generation of iPSCs from MEFs. Mechanistically, c-Jun activates mesenchymal-related genes, broadly suppresses the pluripotent ones, and derails the obligatory mesenchymal to epithelial transition during reprogramming. Furthermore, inhibition of c-Jun by shRNA, dominant-negative c-Jun or Jdp2 enhances reprogramming and replaces Oct4 among the Yamanaka factors. Finally, Jdp2 anchors 5 non-Yamanaka factors (Id1, Jhdm1b, Lrh1, Sall4 and Glis1) to reprogram MEFs into iPSCs. Our studies reveal c-Jun as a guardian of somatic cell fate and its suppression opens the gate to pluripotency.