Journal
RNA
Volume 13, Issue 11, Pages 1894-1910Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.768207
Keywords
target prediction; Dicer knockout; RNAi; miR; mouse embryonic fibroblast
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Vertebrate mRNAs are frequently targeted for post-transcriptional repression by microRNAs ( miRNAs) through mechanisms involving pairing of 39 UTR seed matches to bases at the 59 end of miRNAs. Through analysis of expression array data following miRNA or siRNA overexpression or inhibition, we found that mRNA fold change increases multiplicatively (i.e., log-additively) with seed match count and that a single 8 mer seed match mediates down-regulation comparable to two 7 mer seed matches. We identified several targeting determinants that enhance seed match- associated mRNA repression, including the presence of adenosine opposite miRNA base 1 and of adenosine or uridine opposite miRNA base 9, independent of complementarity to the siRNA/miRNA. Increased sequence conservation in the; 50 bases 59 and 39 of the seed match and increased AU content 39 of the seed match were each independently associated with increased mRNA down-regulation. All of these determinants are enriched in the vicinity of conserved miRNA seed matches, supporting their activity in endogenous miRNA targeting. Together, our results enable improved siRNA off-target prediction, allow integrated ranking of conserved and nonconserved miRNA targets, and show that targeting by endogenous and exogenous miRNAs/siRNAs involves similar or identical determinants.
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