Abstract
The prevailing model of microRNA function is that the "seed region" (nt 2-8) is sufficient to mediate target recognition and repression. However, numerous recent studies have challenged this model, either by demonstrating extensive 3' pairing between physically defined miRNA-mRNA pairs or by showing in Caenorhabditis elegans that disrupted 3' pairing can result in impaired function in vivo. To test the importance of miRNA 3' pairing in a mammalian system in vivo, we engineered a mutant murine mir-146a allele in which the 5' half of the mature microRNA retains its wild-type sequence, but the 3' half's sequence has been altered to robustly disrupt predicted pairing to this latter region. Mice homozygous or hemizygous for this mutant allele are phenotypically indistinguishable from wild-type controls and do not recapitulate any of the immunopathology previously described for mir-146a-null mice. Our results indicate that 3' pairing is dispensable for the established myeloid function of this key mammalian microRNA.
Highlights
MiRNAs are well-established regulators of mRNA stability and translation (Bartel, 2018)
Seminal work by the Burge and Bartel laboratories revealed that the most highly conserved pairing between miRNAs and mRNA 39 UTRs was predicted to occur between nt 2 and 8 of mammalian miRNAs and their mRNA targets (Lewis et al, 2003). This finding was broadly incorporated into a generation of miRNA target prediction algorithms, and several subsequent studies corroborated these initial predictions by showing that the interaction between previously established miRNA–mRNA pairs was dependent upon the seed sequence but, independent of or only marginally reliant on non-seed sequence (Doench & Sharp, 2004; Kloosterman et al, 2004; Brennecke et al, 2005; Lai et al, 2005; Lim et al, 2005)
Some of these latter studies would establish that target sites that contained a seed were typically more effective than sites that did not (Chi et al, 2012; Loeb et al, 2012; Moore et al, 2015). These studies showed that the vast majority of these Argonaute/mRNA interactions incorporated binding beyond the seed, within the 39 region, and a significant proportion of microRNA response elements (MREs) contained no identifiable seed match at all
Summary
MiRNAs are well-established regulators of mRNA stability and translation (Bartel, 2018). The first unbiased identification of bona fide miRNA/mRNA target pairs by physical association of Argonaute proteins with mRNA (Chi et al, 2009) corroborated the predictions of these existing algorithms to some extent by showing that most identified targets contained a seed match, a result which would be echoed by subsequent studies using similar methodologies (Hafner et al, 2010; Chi et al, 2012; Loeb et al, 2012; Grosswendt et al, 2014; Moore et al, 2015; Broughton et al, 2016). This has not previously been genetically addressed in vivo in a mammalian system
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