Goldie Belinda J, Fitzsimmons Chantel, Weidenhofer Judith, Atkins Joshua R, Wang Dan O, Cairns Murray J
School of Biomedical Sciences and Pharmacy, The University of Newcastle, CallaghanNSW, Australia.
Centre for Brain and Mental Health Research, Hunter Medical Research Institute, The University of Newcastle, CallaghanNSW, Australia.
Front Mol Neurosci. 2017 Aug 21;10:259. doi: 10.3389/fnmol.2017.00259. eCollection 2017.
While the cytoplasmic function of microRNA (miRNA) as post-transcriptional regulators of mRNA has been the subject of significant research effort, their activity in the nucleus is less well characterized. Here we use a human neuronal cell model to show that some mature miRNA are preferentially enriched in the nucleus. These molecules were predominantly primate-specific and contained a sequence motif with homology to the consensus MAZ transcription factor binding element. Precursor miRNA containing this motif were shown to have affinity for MAZ protein in nuclear extract. We then used Ago1/2 RIP-Seq to explore nuclear miRNA-associated mRNA targets. Interestingly, the genes for Ago2-associated transcripts were also significantly enriched with MAZ binding sites and neural function, whereas Ago1-transcripts were associated with general metabolic processes and localized with SC35 spliceosomes. These findings suggest the MAZ transcription factor is associated with miRNA in the nucleus and may influence the regulation of neuronal development through Ago2-associated miRNA induced silencing complexes. The MAZ transcription factor may therefore be important for organizing higher order integration of transcriptional and post-transcriptional processes in primate neurons.
虽然作为mRNA转录后调节因子的微小RNA（miRNA）的细胞质功能一直是大量研究工作的主题，但其在细胞核中的活性却鲜为人知。在此，我们使用人类神经元细胞模型来表明一些成熟的miRNA优先富集于细胞核中。这些分子主要是灵长类动物特有的，并且包含一个与共有MAZ转录因子结合元件具有同源性的序列基序。含有该基序的前体miRNA在核提取物中显示出对MAZ蛋白具有亲和力。然后，我们使用AGO1/2 RIP-Seq来探索与细胞核miRNA相关的mRNA靶标。有趣的是，与AGO2相关转录本的基因也显著富集有MAZ结合位点和神经功能，而AGO1转录本则与一般代谢过程相关，并定位于SC35剪接体。这些发现表明MAZ转录因子在细胞核中与miRNA相关，并且可能通过AGO2相关的miRNA诱导沉默复合体影响神经元发育的调控。因此，MAZ转录因子对于组织灵长类神经元中转录和转录后过程的高阶整合可能很重要。
