Regulation of pluripotency in male germline stem cells by Dmrt1.
Regulation of pluripotency in male germline stem cells by Dmrt1.
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DOI：
10.1101/gad.220194.113
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发表时间：
2013-09-15
影响因子：
10.5
通讯作者：
Shinohara T
中科院分区：
文献类型：
--
作者：
Takashima S;Hirose M;Ogonuki N;Ebisuya M;Inoue K;Kanatsu-Shinohara M;Tanaka T;Nishida E;Ogura A;Shinohara T
精原干细胞在特定的培养条件下具有获得多能性的潜能。Takashima等人报道，由Dnmt 1缺失引发的整体DNA低甲基化诱导多能细胞衍生。Dnmt 1缺失下调Dmrt 1，一个参与性别分化的基因。Dmrt 1缺失上调Sox 2，Sox 2又上调Oct 4并产生多能细胞。这些结果表明Dmrt 1-Sox 2轴在抑制SSC多能性中发挥着至关重要的作用。精原干细胞在特定的培养条件下具有获得多能性的潜能。然而，多能细胞衍生的频率较低，并且SSC重编程的机制仍然未知。在这项研究中，我们报告说，在生殖系干细胞（GS）细胞（培养的SSCs）诱导全球DNA低甲基化诱导多能细胞衍生。当Dnmt 1缺失引发DNA去甲基化时，GS细胞发生凋亡。然而，GS细胞通过Dnmt 1和p53的双重敲低转化为胚胎干细胞（ES）样细胞。这种处理下调了Dmrt 1，一个参与性分化，减数分裂和多能性的基因。Dmrt 1耗竭引起GS细胞凋亡，但Dmrt 1和p53耗竭的组合也诱导多能性。推定的Dmrt 1靶基因的功能筛选显示，Dmrt 1耗尽上调Sox 2。Sox 2转染上调Oct 4并产生多能细胞。这种转换增强Oct 1耗尽，表明Oct蛋白的平衡保持SSC身份。这些结果表明，自发SSC重编程是由不稳定的DNA甲基化引起的，并且Dmrt 1-Sox 2级联对于调节SSC中的多能性至关重要。
Spermatogonial stem cells (SSCs) have the potential to acquire pluripotency under specific culture conditions. Takashima et al. report that global DNA hypomethylation triggered by Dnmt1 depletion induces pluripotent cell derivation. Dnmt1 depletion down-regulates Dmrt1, a gene involved in sexual differentiation. Dmrt1 depletion up-regulates Sox2, which in turn up-regulates Oct4 and produces pluripotent cells. These results suggest that the Dmrt1–Sox2 axis plays a crucial role in repression of SSC pluripotency. Spermatogonial stem cells (SSCs) present the potential to acquire pluripotency under specific culture conditions. However, the frequency of pluripotent cell derivation is low, and the mechanism of SSC reprogramming remains unknown. In this study, we report that induction of global DNA hypomethylation in germline stem (GS) cells (cultured SSCs) induces pluripotent cell derivation. When DNA demethylation was triggered by Dnmt1 depletion, GS cells underwent apoptosis. However, GS cells were converted into embryonic stem (ES)-like cells by double knockdown of Dnmt1 and p53. This treatment down-regulated Dmrt1, a gene involved in sexual differentiation, meiosis, and pluripotency. Dmrt1 depletion caused apoptosis of GS cells, but a combination of Dmrt1 and p53 depletion also induced pluripotency. Functional screening of putative Dmrt1 target genes revealed that Dmrt1 depletion up-regulates Sox2. Sox2 transfection up-regulated Oct4 and produced pluripotent cells. This conversion was enhanced by Oct1 depletion, suggesting that the balance of Oct proteins maintains SSC identity. These results suggest that spontaneous SSC reprogramming is caused by unstable DNA methylation and that a Dmrt1–Sox2 cascade is critical for regulating pluripotency in SSCs.
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