Analysis of disease-correlated SNPs in microRNA targets reveals a potential role of RNA structure for microRNA function

MicroRNAs (miRNAs) are evolutionary conserved, endogenous, small single stranded RNAs between 18 and 25 nucleotides in length. They play a major role in post-transcriptional gene regulation accomplished mainly via interactions with the 3’UTR of their target mRNAs. It has been shown that changes of the pattern and expression level of miRNA are significantly involved in pathogenic processes. Furthermore, the occurrence of single nucleotide polymorphisms (SNPs) in miRNAs or miRNA target sites (miR-SNPs) has recently been correlated to several diseases while underlying pathomechanisms remain broadly unresolved.

Here, we study the influence of SNPs in miRNA targets on miRNA-mediated regulation by computer-based and experimental methods. Investigating the secondary structure of polymorphic mRNAs indicates whether SNPs can lead to changes in RNA structure. As RNA-RNA recognition is known to be highly affected by local RNA structure we further experimentally analyzed effects of such structure alterations on miRNA regulation by performing reporter gene assays as well as RNA probing.

The observations described in this study are compatible with a model in which a SNP affects local RNA structure which is related to altered characteristics of the binding between miRNA and target mRNA. This model seems to be valid even in cases in which a SNP is not within but rather neighboring a miRNA target stretch. In conclusion, we consider SNP-induced changes of RNA structure as an important mechanism underlying the role of miR‑SNPs with regard to aberrant cellular processes.