MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation
MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation
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DOI：
10.1038/nature07880
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发表时间：
2009
期刊：
影响因子：
64.8
通讯作者：
Yvonne Tay;Jinqiu Zhang;A. Thomson;B. Lim;I. Rigoutsos
中科院分区：
文献类型：
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作者：
Yvonne Tay;Jinqiu Zhang;A. Thomson;B. Lim;I. Rigoutsos
microRNA（miRNAs）是一种短RNA，以序列依赖的方式指导信使RNA降解或破坏mRNA翻译，。十多年来，研究miRNA与其靶点相互作用的尝试仅限于mRNA的3′非翻译区，这助长了一个潜在的假设，即这些区域是miRNA活性的主要接受者。在此，我们重点研究了小鼠Nanog、Oct 4（也称为Pou 5 f1）和Sox 2基因，并证明了在它们的氨基酸编码序列（CDS）中存在许多天然存在的miRNA靶点。分析的一些小鼠靶标不包含miRNA种子，而另一些跨越外显子-外显子连接或在人类和恒河猴基因组中不保守。在视黄酸诱导的小鼠胚胎干细胞分化中上调的miR-134、miR-296和miR-470以各种组合靶向每个转录因子的CDS，导致分化小鼠胚胎干细胞的转录和形态学特征变化，并导致新的表型。预测靶点的沉默突变消除了miRNA活性，阻止了相应基因的下调，并延迟了诱导的表型。我们的研究结果证明了大量位于CDS的miRNA靶点，其中一些可以是物种特异性的，并支持一个增强的模型，即动物miRNA通过可以位于3′非翻译区之外的靶点对mRNA进行控制。
MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner,,,,,,. For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3′ untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouseNanog,Oct4(also known asPou5f1) andSox2genes,,,and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon–exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3′ untranslated region.