IsomiRs: Expanding the miRNA repression toolbox beyond the seed

Abstract MicroRNAs (miRNAs) are a class of small non-coding RNAs that play increasingly appreciated roles in gene regulation. In animals, miRNAs silence gene expression by binding to partially complementary sequences within target mRNAs. It is well-established that miRNAs recognize canonical target sites by base-pairing in the 5′region. However, the development of biochemical methods has identified many novel, non-canonical target sites, suggesting additional modes of miRNA-target association. Here, we review the current knowledge of miRNA-target recognition and how new evidence supports or challenges existing models. We also review the process by which microRNA isoforms achieve functional diversification via modulation of target recognition.