Abstract
miRNAs are small RNAs that are key regulators of gene expression in eukaryotic organisms. The processing of miRNAs is regulated by structural characteristics of the RNA and is also tightly controlled by auxiliary protein factors. Among them, RNA binding proteins play crucial roles to facilitate or inhibit miRNA maturation and can be controlled in a cell, tissue and species-specific manners or in response to environmental stimuli. In this study we dissect the molecular mechanism that promotes the overexpression of miR-132 in mice over its related, co-transcribed and co-regulated miRNA, miR-212. We have shown that the loop structure of miR-132 is a key determinant for its efficient processing in cells. We have also identified a range of RNA binding proteins that recognize the loop of miR-132 and influence both miR-132 and miR-212 processing. The DEAD box helicase p72/DDX17 was identified as a factor that facilitates the specific processing of miR-132.
Highlights
An increasing amount of evidence shows that the steady state level of miRNAs are post-transcriptionally regulated at diverse steps of miRNA maturation[8]
We have previously reported that there is a significant difference between the steady state levels of mature miR-132 and miR-212 in primary cortical neurons isolated from mice, in spite of the fact that they are co-transcribed in the same intron of a non coding gene[30]
Based on our detection of the mature miRNAs using Northern blotting and the GFP expression we concluded that the RNA transcribed from the reporter plasmid is properly spliced and both miRNAs were accurately processed in human HeLa and mouse neuroblastoma cells (Supplementary Figure 1A)
Summary
An increasing amount of evidence shows that the steady state level of miRNAs are post-transcriptionally regulated at diverse steps of miRNA maturation[8]. We identified multiple RNA binding proteins that bind the loop sequence of miR-132 and influence miRNA processing. One of these proteins is the DEAD box RNA helicase p72/DDX17 which, together with the highly related p68/DDX5 protein, is associated with the Drosha complex and is required for processing of specific subsets of miRNAs3,9. Our data show that p72/DDX17 interacts with the miR-132 loop sequence and influences the relative ratio of the mature mice miR-212/132 miRNAs
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