Sir William Dunn School of Pathology, Oxford, UK.
Cell Cycle. 2010 Feb 1;9(3):531-9. doi: 10.4161/cc.9.3.10511.
The nuclear envelope can regulate gene expression through its interaction with chromatin and by the sequestration of specific transcription factors. In this study, we show that such regulation can be achieved via microRNA regulation. We identify a set of miRNAs that are dysregulated in the absence of a fully functional nuclear lamina. We then focus on miRNA-31 and experimentally confirm its targets. The target set identified is significantly enriched in genes involved in controlling progress through the cell cycle such as Cdkn2a. Normalizing miRNA-31 levels, either using a specific inhibitor or by restoration of the nuclear lamina, also normalizes cell cycle distribution and cell proliferation rates. We show that the 3'UtR of p16(Ink4a)/p19(Arf) has a functional miRNA-31 binding site which contributes to the observed regulation of cell cycle progression. Our findings are the first demonstration that the nuclear envelope can control gene expression by regulating specific miRNA levels, and that miRNA-31 is involved in the regulation of cell proliferation and progress through the cell cycle at least in part by regulating the levels of p16(Ink4a)/p19(Arf).
核膜可以通过与染色质相互作用和隔离特定转录因子来调节基因表达。在这项研究中，我们表明这种调节可以通过 microRNA 调节来实现。我们确定了一组在没有完全功能的核层的情况下失调的 microRNAs。然后，我们专注于 microRNA-31 并通过实验证实了其靶标。鉴定的靶标集在参与控制细胞周期进程的基因中显著富集，例如 Cdkn2a。通过使用特异性抑制剂或恢复核层来正常化 microRNA-31 水平，也可以使细胞周期分布和细胞增殖率正常化。我们表明，p16(Ink4a)/p19(Arf) 的 3'UTR 具有功能性的 microRNA-31 结合位点，这有助于观察到对细胞周期进程的调节。我们的发现首次证明核膜可以通过调节特定的 microRNA 水平来控制基因表达，并且 microRNA-31 通过调节 p16(Ink4a)/p19(Arf) 的水平至少部分参与调节细胞增殖和细胞周期进程。
