title: Transcriptome-wide miR-155 binding map reveals widespread noncanonical microRNA targeting.
abstract: MicroRNAs (miRNAs) are essential components of gene regulation, but identification of miRNA targets remains a major challenge. Most target prediction and discovery relies on perfect complementarity of the miRNA seed to the 3' untranslated region (UTR). However, it is unclear to what extent miRNAs target sites without seed matches. Here, we performed a transcriptome-wide identification of the endogenous targets of a single miRNA-miR-155-in a genetically controlled manner. We found that approximately 40% of miR-155-dependent Argonaute binding occurs at sites without perfect seed matches. The majority of these noncanonical sites feature extensive complementarity to the miRNA seed with one mismatch. These noncanonical sites confer regulation of gene expression, albeit less potently than canonical sites. Thus, noncanonical miRNA binding sites are widespread, often contain seed-like motifs, and can regulate gene expression, generating a continuum of targeting and regulation.
authors.affiliation: Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Gabriel B
authors.initials: GB
authors.lastname: Loeb
authors.forename: Aly A
authors.initials: AA
authors.lastname: Khan
authors.forename: David
authors.initials: D
authors.lastname: Canner
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Hiatt
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
authors.forename: Christina S
authors.initials: CS
authors.lastname: Leslie
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D019295:Computational Biology; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D059372:Nucleotide Motifs; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D059467:Transcriptome; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D060565:Argonaute Proteins; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D012333:RNA, Messenger