title: Divergent target recognition by coexpressed 5'-isomiRs of miR-142-3p and selective viral mimicry.
abstract: Sequence heterogeneity at the ends of mature microRNAs (miRNAs) is well documented, but its effects on miRNA function are largely unexplored. Here we studied the impact of miRNA 5'-heterogeneity, which affects the seed region critical for target recognition. Using the example of miR-142-3p, an emerging regulator of the hematopoietic lineage in vertebrates, we show that naturally coexpressed 5'-variants (5'-isomiRs) can recognize largely distinct sets of binding sites. Despite this, both miR-142-3p isomiRs regulate exclusive and shared targets involved in actin dynamics. Thus, 5'-heterogeneity can substantially broaden and enhance regulation of one pathway. Other 5'-isomiRs, in contrast, recognize largely overlapping sets of binding sites. This is exemplified by two herpesviral 5'-isomiRs that selectively mimic one of the miR-142-3p 5'-isomiRs. We hypothesize that other cellular and viral 5'-isomiRs can similarly be grouped into those with divergent or convergent target repertoires, based on 5'-sequence features. Taken together, our results provide a detailed characterization of target recognition by miR-142-3p and its 5'-isomiR-specific viral mimic. We furthermore demonstrate that miRNA 5'-end variation leads to differential targeting and can thus broaden the target range of miRNAs.
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Manzano
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Forte
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Archana N
authors.initials: AN
authors.lastname: Raja
authors.affiliation: Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schipma
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Gottwein
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005260:Female; D018740:Genetic Heterogeneity; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D013045:Species Specificity
chemical_list: D000199:Actins; D035683:MicroRNAs; D012367:RNA, Viral
keywords: Kaposi's sarcoma associated herpesvirus; isomiR; miR-142-3p; miR-K10a; miRNA