Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
Stem Cell Reports. 2014 Feb 20;2(3):351-65. doi: 10.1016/j.stemcr.2014.01.005. eCollection 2014 Mar 11.
Differentiated cells can be reprogrammed into induced pluripotent stem cells (iPSCs) after overexpressing four transcription factors, of which Oct4 is essential. To elucidate the role of Oct4 during reprogramming, we investigated the immediate transcriptional response to inducible Oct4 overexpression in various somatic murine cell types using microarray analysis. By downregulating somatic-specific genes, Oct4 induction influenced each transcriptional program in a unique manner. A significant upregulation of pluripotent markers could not be detected. Therefore, OCT4 facilitates reprogramming by interfering with the somatic transcriptional network rather than by directly initiating a pluripotent gene-expression program. Finally, Oct4 overexpression upregulated the gene Mgarp in all the analyzed cell types. Strikingly, Mgarp expression decreases during the first steps of reprogramming due to a KLF4-dependent inhibition. At later stages, OCT4 counteracts the repressive activity of KLF4, thereby enhancing Mgarp expression. We show that this temporal expression pattern is crucial for the efficient generation of iPSCs.
分化细胞在过表达四种转录因子后可被重编程为诱导多能干细胞（iPSCs），其中 Oct4 是必需的。为了阐明 Oct4 在重编程过程中的作用，我们使用微阵列分析研究了在各种体细胞核细胞类型中瞬时转录因子 Oct4 过表达的直接转录反应。通过下调体细胞特异性基因，Oct4 的诱导以独特的方式影响每个转录程序。未检测到多能标记的显著上调。因此，OCT4 通过干扰体细胞转录网络而不是直接启动多能基因表达程序来促进重编程。最后，Oct4 过表达上调了所有分析细胞类型中的基因 Mgarp。引人注目的是，由于 KLF4 依赖性抑制，Mgarp 在重编程的早期阶段表达降低。在后期，OCT4 会抵消 KLF4 的抑制活性，从而增强 Mgarp 的表达。我们表明，这种时间表达模式对于 iPSCs 的有效生成至关重要。
