Xu Na, Papagiannakopoulos Thales, Pan Guangjin, Thomson James A, Kosik Kenneth S
Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, The University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
Cell. 2009 May 15;137(4):647-58. doi: 10.1016/j.cell.2009.02.038. Epub 2009 Apr 30.
MicroRNAs (miRNAs) are posttranscriptional modulators of gene expression and play an important role in many developmental processes. We report here that expression of microRNA-145 (miR-145) is low in self-renewing human embryonic stem cells (hESCs) but highly upregulated during differentiation. We identify the pluripotency factors OCT4, SOX2, and KLF4 as direct targets of miR-145 and show that endogenous miR-145 represses the 3' untranslated regions of OCT4, SOX2, and KLF4. Increased miR-145 expression inhibits hESC self-renewal, represses expression of pluripotency genes, and induces lineage-restricted differentiation. Loss of miR-145 impairs differentiation and elevates OCT4, SOX2, and KLF4. Furthermore, we find that the miR-145 promoter is bound and repressed by OCT4 in hESCs. This work reveals a direct link between the core reprogramming factors and miR-145 and uncovers a double-negative feedback loop involving OCT4, SOX2, KLF4, and miR-145.
微小RNA（miRNA）是基因表达的转录后调节因子，在许多发育过程中发挥重要作用。我们在此报告，微小RNA - 145（miR - 145）在自我更新的人类胚胎干细胞（hESC）中表达较低，但在分化过程中高度上调。我们确定多能性因子OCT4、SOX2和KLF4为miR - 145的直接靶标，并表明内源性miR - 145抑制OCT4、SOX2和KLF4的3'非翻译区。miR - 145表达增加会抑制hESC自我更新，抑制多能性基因的表达，并诱导谱系限制性分化。miR - 145缺失会损害分化并提高OCT4、SOX2和KLF4的水平。此外，我们发现miR - 145启动子在hESC中被OCT4结合并抑制。这项工作揭示了核心重编程因子与miR - 145之间的直接联系，并揭示了一个涉及OCT4、SOX2、KLF4和miR - 145的双负反馈回路。
