title: Anti-miRs competitively inhibit microRNAs in Argonaute complexes.
abstract: MicroRNAs (miRNAs), small RNA molecules that post-transcriptionally regulate mRNA expression, are crucial in diverse developmental and physiological programs and their misregulation can lead to disease. Chemically modified oligonucleotides have been developed to modulate miRNA activity for therapeutic intervention in disease settings, but their mechanism of action has not been fully elucidated. Here we show that the miRNA inhibitors (anti-miRs) physically associate with Argonaute proteins in the context of the cognate target miRNA in vitro and in vivo. The association is mediated by the seed region of the miRNA and is sensitive to the placement of chemical modifications. Furthermore, the targeted miRNAs are stable and continue to be associated with Argonaute. Our results suggest that anti-miRs specifically associate with Argonaute-bound miRNAs, preventing association with target mRNAs, which leads to subsequent stabilization and thus increased expression of the targeted mRNAs.
authors.affiliation: Regulus Therapeutics, San Diego, California, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hogan
authors.affiliation: Regulus Therapeutics, San Diego, California, United States of America.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Vincent
authors.affiliation: Regulus Therapeutics, San Diego, California, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fish
authors.affiliation: Regulus Therapeutics, San Diego, California, United States of America.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Marcusson
authors.affiliation: Regulus Therapeutics, San Diego, California, United States of America.
authors.forename: Balkrishen
authors.initials: B
authors.lastname: Bhat
authors.affiliation: Regulus Therapeutics, San Diego, California, United States of America.
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
authors.affiliation: Regulus Therapeutics, San Diego, California, United States of America.
authors.forename: Dimitrios G
authors.initials: DG
authors.lastname: Zisoulis
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects
chemical_list: D060565:Argonaute Proteins; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense