title: Unusually effective microRNA targeting within repeat-rich coding regions of mammalian mRNAs.
abstract: MicroRNAs (miRNAs) regulate numerous biological processes by base-pairing with target messenger RNAs (mRNAs), primarily through sites in 3' untranslated regions (UTRs), to direct the repression of these targets. Although miRNAs have sometimes been observed to target genes through sites in open reading frames (ORFs), large-scale studies have shown such targeting to be generally less effective than 3' UTR targeting. Here, we show that several miRNAs each target significant groups of genes through multiple sites within their coding regions. This ORF targeting, which mediates both predictable and effective repression, arises from highly repeated sequences containing miRNA target sites. We show that such sequence repeats largely arise through evolutionary duplications and occur particularly frequently within families of paralogous C(2)H(2) zinc-finger genes, suggesting the potential for their coordinated regulation. Examples of ORFs targeted by miR-181 include both the well-known tumor suppressor RB1 and RBAK, encoding a C(2)H(2) zinc-finger protein and transcriptional binding partner of RB1. Our results indicate a function for repeat-rich coding sequences in mediating post-transcriptional regulation and reveal circumstances in which miRNA-mediated repression through ORF sites can be reliably predicted.
authors.affiliation: Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schnall-Levin
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Rissland
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Johnston
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
authors.forename: David P
authors.initials: DP
authors.lastname: Bartel
authors.forename: Bonnie
authors.initials: B
authors.lastname: Berger
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D020440:Gene Duplication; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics*; D012333:RNA, Messenger / Q000737:chemistry*; D012091:Repetitive Sequences, Nucleic Acid; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger