The m6A modification has been implicated as an important epitranscriptomic marker, which plays extensive roles in the regulation of transcript stability, splicing, translation, and localization. Nevertheless, only some genes are repeatedly modified across various conditions and the principle of m6A regulation remains elusive. In this study, we performed a systems-level analysis of human genes frequently regulated by m6A modification (m6Afreq genes) and those occasionally regulated by m6A modification (m6Aocca genes). Compared to the m6Aocca genes, the m6Afreq genes exhibit gene importance-related features, such as lower dN/dS ratio, higher protein–protein interaction network degree, and reduced tissue expression specificity. Signaling network analysis indicates that the m6Afreq genes are associated with downstream components of signaling cascades, high-linked signaling adaptors, and specific network motifs like incoherent feed forward loops. Moreover, functional enrichment analysis indicates significant overlaps between the m6Afreq genes and genes involved in various layers of gene expression, such as being the microRNA targets and the regulators of RNA processing. Therefore, our findings suggest the potential interplay between m6A epitranscriptomic regulation and other gene expression regulatory machineries.
正如DNA和组蛋白修饰作为DNA水平上的表观遗传调控的核心组分一样，RNA腺嘌呤碱基上第6位N上的甲基化修饰（即m6A修饰）也是一种关键的、RNA水平上的表观遗传修饰。m6A甲基化修饰被发现能够调控转录本稳定性、可变剪接、翻译、定位等重要生物过程。然而，目前m6A调控的机制尚未完全解明。随着高通量RNA m6A甲基化测序（MeRIP-seq）数据的积累，我们现在可以通过生物信息学方法比较不同实验得到的m6A甲基化谱，挖掘其中潜在的调控规律。有意思的是，我们通过对现有人类m6A甲基化谱数据的整理发现，只有少数基因能够在多种情况下被反复修饰，而这一现象背后的原理仍不清楚。在本工作中，我们系统比较分析了在多种情况下频繁和偶尔发生m6A修饰的基因。相对于偶尔发生m6A修饰的基因而言，频繁发生m6A修饰的基因表现出一些与基因重要性有关的特征，如更低的dN/dS比率，更高的蛋白互作网络的度，更低的组织表达特异性等。这说明重要基因倾向于受到m6A修饰调控。而信号转导网络分析则提示，频繁发生m6A修饰的基因倾向于作为信号转导通路的下游组分、高度连接的信号转导接头蛋白、以及一些特殊网络模体（如非协调的前馈环）的成员出现。m6A这种信号转导网络的拓扑特征与miRNA靶基因在信号转导网络的拓扑特征有一定相似性。确实，功能富集分析进一步表明频繁发生m6A修饰的基因与microRNA靶基因、参与到RNA加工调控的基因等存在显著重叠。因此，我们的分析结果提示m6A表观转录组调控与其它基因表达调控机制存在潜在的功能关联与互动。





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