Reprogramming Factor Stoichiometry Influences the Epigenetic State and Biological Properties of Induced Pluripotent Stem Cells
Reprogramming Factor Stoichiometry Influences the Epigenetic State and Biological Properties of Induced Pluripotent Stem Cells
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DOI：
10.1016/j.stem.2011.11.003
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发表时间：
2011-12-02
期刊：
影响因子：
23.9
通讯作者：
Jaenisch, Rudolf
中科院分区：
文献类型：
--
作者：
Carey, Bryce W.;Markoulaki, Styliani;Jaenisch, Rudolf
我们比较了两个遗传上高度定义的转基因系统，以确定影响体细胞重编程为多能状态的参数。我们的研究结果表明，在重编程过程中重编程因子的水平和化学计量强烈影响iPS细胞的多能性。Oct 4和Klf 4的高表达与c-Myc和Sox 2的低表达相结合产生了iPS细胞，该iPS细胞通过四倍体（4 n）互补有效地产生了“全iPSC小鼠”，在Dlk 1-Dio 3基因座处保持了正常的印记，并且没有产生具有肿瘤的小鼠。在Dlk 1-Dio 3基因座处的印记（LOI）的丧失与降低的多能性不严格相关，尽管产生“全iPSC小鼠”的效率降低。我们的数据表明，重编程因子的化学计量可以影响iPS细胞的表观遗传和生物学特性。这一概念使定义iPSC和ESC的“通用”表观遗传状态的努力复杂化，并且在比较不同的iPS和ES细胞系时应加以考虑。
We compared two genetically highly defined transgenic systems to identify parameters affecting reprogramming of somatic cells to a pluripotent state. Our results demonstrate that the level and stoichiometry of reprogramming factors during the reprogramming process strongly influence the resulting pluripotency of iPS cells. High expression of Oct4 and Klf4 combined with lower expression of c-Myc and Sox2 produced iPS cells that efficiently generated "all-iPSC mice" by tetraploid (4n) complementation, maintained normal imprinting at the Dlk1-Dio3 locus, and did not create mice with tumors. Loss of imprinting (LOI) at the Dlk1-Dio3 locus did not strictly correlate with reduced pluripotency though the efficiency of generating "all-iPSC mice" was diminished. Our data indicate that stoichiometry of reprogramming factors can influence epigenetic and biological properties of iPS cells. This concept complicates efforts to define a "generic" epigenetic state of iPSCs and ESCs and should be considered when comparing different iPS and ES cell lines.