Competing endogenous RNA crosstalk at system level

microRNAs (miRNAs) regulate gene expression at post-transcriptional level by repressing target RNA molecules. Competition to bind miRNAs tends in turn to correlate their targets, establishing effective RNA-RNA interactions that can influence expression levels, buffer fluctuations and promote signal propagation. Such a potential has been characterized mathematically for small motifs both at steady state and away from stationarity. Experimental evidence, on the other hand, suggests that competing endogenous RNA (ceRNA) crosstalk is rather weak. Extended miRNA-RNA networks could however favour the integration of many crosstalk interactions, leading to significant large-scale effects in spite of the weakness of individual links. To clarify the extent to which crosstalk is sustained by the miRNA interactome, we have studied its emergent systemic features in silico in large-scale miRNA-RNA network reconstructions. We show that, although generically weak, system-level crosstalk patterns (i) are enhanced by transcriptional heterogeneities, (ii) can achieve high-intensity even for RNAs that are not co-regulated, (iii) are robust to variability in transcription rates, and (iv) are significantly non-local, i.e. correlate weakly with miRNA-RNA interaction parameters. Furthermore, RNA levels are generically more stable when crosstalk is strongest. As some of these features appear to be encoded in the network’s topology, crosstalk may functionally be favoured by natural selection. These results suggest that, besides their repressive role, miRNAs mediate a weak but resilient and context-independent network of cross-regulatory interactions that interconnect the transcriptome, stabilize expression levels and support system-level responses.

微小RNA（microRNAs, miRNAs）通过抑制靶RNA分子，在转录后水平调控基因表达。结合miRNA的竞争反过来会使其靶标产生关联，形成可影响表达水平、缓冲波动并促进信号传导的有效RNA-RNA相互作用。这类功能潜力已针对小型基序，在稳态与非稳态条件下完成了数学表征。另一方面，实验证据显示，内源竞争RNA（competing endogenous RNA, ceRNA）串扰整体强度较弱。然而，扩展的miRNA-RNA网络或可促进大量串扰相互作用的整合，即便单个连接的强度较弱，也能催生显著的大规模效应。为阐明miRNA相互作用组能够维持串扰的程度，我们通过大规模miRNA-RNA网络重构的计算机模拟（in silico），探究了其涌现的系统级特征。研究结果表明：尽管串扰整体偏弱，但系统级串扰模式具备四大特征：（i）可因转录异质性而增强；（ii）即便对于非共调控的RNA，也能达到较高强度；（iii）对转录速率变异具有鲁棒性；（iv）具有显著的非局部性，即与miRNA-RNA相互作用参数关联微弱。此外，当串扰达到最强时，RNA水平整体更趋稳定。由于部分特征似乎由网络拓扑结构编码，串扰或可在自然选择中获得功能层面的正向偏好。本研究结果提示，除其固有的抑制性功能外，miRNAs还介导了一个微弱但具有鲁棒性、且不依赖于上下文的交叉调控相互作用网络——该网络连接整个转录组、稳定基因表达水平并支撑系统级响应。