Widespread context-dependency of microRNA-mediated regulation

Abstract

Gene expression is regulated in a context-dependent, cell-type specific manner. Condition-specific transcription is dependent on the presence of transcription factors (TFs) that can activate or inhibit its target genes (global context). Additional factors such as chromatin structure, histone or DNA modifications also influence the activity of individual target genes (individual context). The role of the global and individual context for post-transcriptional regulation has not systematically been investigated on a large-scale and is poorly understood. Here we show that global and individual context-dependency is a pervasive feature of microRNA-mediated regulation. Our comprehensive and highly consistent dataset from several high-throughput technologies (PAR-CLIP, RIP-Chip, 4sU-tagging and SILAC) provides strong evidence that context-dependent microRNA target sites (CDTS) are as frequent and functionally relevant as constitutive target sites (CTS). Furthermore, we found the global context to be insufficient to explain the CDTS and that flanking sequence motifs provide individual context that is an equally important factor. Our results demonstrate that, similar to TF-mediated regulation, global and individual context-dependency are prevalent in microRNA-mediated gene regulation implying a much more complex post-transcriptional regulatory network than currently known. The necessary tools to unravel post-transcriptional regulations and mechanisms need to be much more involved and much more data will be needed for particular cell types and cellular conditions to understand microRNA-mediated regulation and the context-dependent post-transcriptional regulatory network.