Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
1] Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA. [2] Howard Hughes Medical Institute, Stanford, California, USA.
Nat Struct Mol Biol. 2014 Jul;21(7):585-90. doi: 10.1038/nsmb.2842. Epub 2014 Jun 15.
Long noncoding RNAs (lncRNAs) are important regulators of cell fate, yet little is known about mechanisms controlling lncRNA expression. Here we show that transcription is quantitatively different for lncRNAs and mRNAs--as revealed by deficiency of Dicer (Dcr), a key RNase that generates microRNAs (miRNAs). Dcr loss in mouse embryonic stem cells led unexpectedly to decreased levels of hundreds of lncRNAs. The canonical Dgcr8-Dcr-miRNA pathway is required for robust lncRNA transcriptional initiation and elongation. Computational and genetic epistasis analyses demonstrated that Dcr activation of the oncogenic transcription factor cMyc is partly responsible for lncRNA expression. A quantitative metric of mRNA-lncRNA decoupling revealed that Dcr and cMyc differentially regulate lncRNAs versus mRNAs in diverse cell types and in vivo. Thus, numerous lncRNAs may be modulated as a class in development and disease, notably where Dcr and cMyc act.
长非编码 RNA（lncRNA）是细胞命运的重要调节因子，但对于控制 lncRNA 表达的机制知之甚少。在这里，我们表明转录在 lncRNA 和 mRNA 之间存在定量差异——这是由关键的核糖核酸酶 Dicer（Dcr）缺乏引起的，Dcr 是生成 microRNA（miRNA）的关键酶。在小鼠胚胎干细胞中缺乏 Dcr 会导致数百个 lncRNA 水平意外降低。典型的 Dgcr8-Dcr-miRNA 途径是 lncRNA 转录起始和延伸所必需的。计算和遗传上位性分析表明，Dcr 激活致癌转录因子 cMyc 部分负责 lncRNA 的表达。mRNA-lncRNA 解耦的定量指标表明，Dcr 和 cMyc 在不同细胞类型和体内以不同的方式调节 lncRNA 与 mRNA。因此，在发育和疾病中，许多 lncRNA 可能作为一类被调节，特别是在 Dcr 和 cMyc 起作用的情况下。
