State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
Cell. 2013 Jan 17;152(1-2):82-96. doi: 10.1016/j.cell.2012.11.045. Epub 2013 Jan 11.
The induction of pluripotency or trans-differentiation of one cell type to another can be accomplished with cell-lineage-specific transcription factors. Here, we report that repression of a single RNA binding polypyrimidine-tract-binding (PTB) protein, which occurs during normal brain development via the action of miR-124, is sufficient to induce trans-differentiation of fibroblasts into functional neurons. Besides its traditional role in regulated splicing, we show that PTB has a previously undocumented function in the regulation of microRNA functions, suppressing or enhancing microRNA targeting by competitive binding on target mRNA or altering local RNA secondary structure. A key event during neuronal induction is the relief of PTB-mediated blockage of microRNA action on multiple components of the REST complex, thereby derepressing a large array of neuronal genes, including miR-124 and multiple neuronal-specific transcription factors, in nonneuronal cells. This converts a negative feedback loop to a positive one to elicit cellular reprogramming to the neuronal lineage.
通过细胞谱系特异性转录因子，可以诱导多能性或一种细胞类型向另一种细胞类型的转分化。在这里，我们报告说，通过 miR-124 的作用，抑制一种单一的 RNA 结合多嘧啶-tract 结合（PTB）蛋白的表达，在正常脑发育过程中足以诱导成纤维细胞向功能性神经元的转分化。除了其在调节剪接中的传统作用外，我们还表明，PTB 在调节 microRNA 功能方面具有以前未被记录的作用，通过在靶 mRNA 上竞争结合或改变局部 RNA 二级结构来抑制或增强 microRNA 的靶向作用。神经元诱导过程中的一个关键事件是解除 PTB 介导的 microRNA 对 REST 复合物多个成分的作用的阻断，从而解除非神经元细胞中许多神经元基因的抑制，包括 miR-124 和多个神经元特异性转录因子。这将负反馈环转换为正反馈环，引发细胞重编程到神经元谱系。
