Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
Elife. 2020 Nov 11;9:e58478. doi: 10.7554/eLife.58478.
Circular RNAs are important for many cellular processes but their mechanisms of action remain poorly understood. Here, we map circRNA inventories of mouse embryonic stem cells, neuronal progenitor cells and differentiated neurons and identify hundreds of highly expressed circRNAs. By screening several candidate circRNAs for a potential function in neuronal differentiation, we find that represses expression of key neuronal markers, suggesting that this molecule negatively regulates neuronal differentiation. Among 760 tested genes linked to known neuronal pathways, knockdown of deregulates expression of numerous genes including nerve growth factor receptor (), which becomes transcriptionally upregulated to enhance NGF signaling. We identify a -nucleated transcription-repressive complex containing hnRNP-K/L proteins and show that knockdown of these factors strongly augments NGFR regulation. Finally, we show that the ZNF827 protein is part of the mRNP complex, suggesting a functional co-evolution of a circRNA and the protein encoded by its linear pre-mRNA host.
环状 RNA 对于许多细胞过程都很重要，但它们的作用机制仍知之甚少。在这里，我们绘制了小鼠胚胎干细胞、神经祖细胞和分化神经元的环状 RNA 图谱，并鉴定了数百种高表达的环状 RNA。通过筛选几个候选环状 RNA 在神经元分化中的潜在功能，我们发现 抑制关键神经元标记物的表达，表明该分子负调控神经元分化。在与已知神经元途径相关的 760 个测试基因中， 下调可调节包括神经生长因子受体 (NGFR) 在内的众多基因的表达，NGFR 转录上调以增强 NGF 信号。我们鉴定了一个包含 hnRNP-K/L 蛋白的 -核转录抑制复合物，并表明这些因子的下调可强烈增强 NGFR 调节。最后，我们表明 ZNF827 蛋白是 mRNP 复合物的一部分，这表明环状 RNA 和其线性前体 mRNA 编码蛋白的功能共同进化。
