Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, Howard Hughes Medical Institute, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
J Biol Chem. 2010 Aug 13;285(33):25516-21. doi: 10.1074/jbc.M110.142059. Epub 2010 Jun 16.
Recent studies have demonstrated that embryonic stem cell-like induced pluripotent stem (iPS) cells can be generated by enforced expression of defined transcription factors. The fact that cell fate change is accompanied by changes in epigenetic modifications prompted us to investigate whether chemicals known to modulate epigenetic regulators are capable of enhancing the efficiency of iPS cell generation. Here, we report that butyrate, a natural small fatty acid and histone deacetylase inhibitor, significantly increases the efficiency of mouse iPS cell generation using the transcription factors Oct4, Sox2, Klf4, and c-Myc. We show that butyrate not only changes the reprogramming dynamics, but also increases the ratio of iPS cell colonies to total colonies by reducing the frequency of partially reprogrammed cells and transformed cells. Detailed analysis reveals that the effect of butyrate on reprogramming appears to be mediated by c-Myc and occurs during an early stage of reprogramming. Genome-wide gene expression analysis reveals up-regulation of ES cell-enriched genes when mouse embryonic fibroblasts are treated with butyrate during reprogramming. Thus, our study identifies butyrate as a chemical factor capable of promoting iPS cell generation.
最近的研究表明，通过强制表达特定的转录因子，可以产生胚胎干细胞样诱导多能干细胞（iPS 细胞）。事实上，细胞命运的改变伴随着表观遗传修饰的改变，这促使我们研究是否已知能调节表观遗传调节剂的化学物质能够提高 iPS 细胞生成的效率。在这里，我们报告丁酸，一种天然的小分子脂肪酸和组蛋白去乙酰化酶抑制剂，能够显著提高使用转录因子 Oct4、Sox2、Klf4 和 c-Myc 生成小鼠 iPS 细胞的效率。我们表明，丁酸不仅改变了重编程动力学，而且通过降低部分重编程细胞和转化细胞的频率，增加了 iPS 细胞集落与总集落的比例。详细分析表明，丁酸对重编程的影响似乎是由 c-Myc 介导的，并发生在重编程的早期阶段。全基因组基因表达分析显示，在用丁酸处理胚胎成纤维细胞进行重编程时，ES 细胞丰富的基因上调。因此，我们的研究确定丁酸是一种能够促进 iPS 细胞生成的化学因子。
