3′ Uridylation Confers miRNAs with Non-canonical Target Repertoires

TY - JOUR

T1 - 3′ Uridylation Confers miRNAs with Non-canonical Target Repertoires

AU - Yang, A.

AU - Bofill-De Ros, Xavier

AU - Shao, Tie Juan

AU - Jiang, Minjie

AU - Li, Katherine

AU - Villanueva, Patricia

AU - Dai, Lisheng

AU - Gu, Shuo

N1 - Publisher Copyright: © 2019

PY - 2019/8/8

Y1 - 2019/8/8

N2 - Many microRNAs (miRNAs) exist alongside abundant miRNA isoforms (isomiRs), most of which arise from post-maturation sequence modifications such as 3′ uridylation. However, the ways in which these sequence modifications affect miRNA function remain poorly understood. Here, using human miR-27a in cell lines as a model, we discovered that a nonfunctional target site unable to base-pair extensively with the miRNA seed sequence can regain function when an upstream adenosine is able to base-pair with a post-transcriptionally added uridine in the miR-27a tail. This tail-U-mediated repression (TUMR) is abolished in cells lacking the uridylation enzymes TUT4 and TUT7, indicating that uridylation alters miRNA function by modulating target recognition. We identified a set of non-canonical targets in human cells that are specifically regulated by uridylated miR-27a. We provide evidence that TUMR expands the targets of other endogenous miRNAs. Our study reveals a function of uridylated isomiRs in regulating non-canonical miRNA targets. Yang et al. demonstrate that mRNAs lacking a seed pairing are repressed by miR-27a because of base-pairing between an upstream adenosine in the target and a non-templated U tail in miR-27a. They identify a large class of non-canonical targets regulated by uridylated miRNAs and reveal a novel function of 3′ isomiRs.

AB - Many microRNAs (miRNAs) exist alongside abundant miRNA isoforms (isomiRs), most of which arise from post-maturation sequence modifications such as 3′ uridylation. However, the ways in which these sequence modifications affect miRNA function remain poorly understood. Here, using human miR-27a in cell lines as a model, we discovered that a nonfunctional target site unable to base-pair extensively with the miRNA seed sequence can regain function when an upstream adenosine is able to base-pair with a post-transcriptionally added uridine in the miR-27a tail. This tail-U-mediated repression (TUMR) is abolished in cells lacking the uridylation enzymes TUT4 and TUT7, indicating that uridylation alters miRNA function by modulating target recognition. We identified a set of non-canonical targets in human cells that are specifically regulated by uridylated miR-27a. We provide evidence that TUMR expands the targets of other endogenous miRNAs. Our study reveals a function of uridylated isomiRs in regulating non-canonical miRNA targets. Yang et al. demonstrate that mRNAs lacking a seed pairing are repressed by miR-27a because of base-pairing between an upstream adenosine in the target and a non-templated U tail in miR-27a. They identify a large class of non-canonical targets regulated by uridylated miRNAs and reveal a novel function of 3′ isomiRs.

KW - isomiRs

KW - miR-27a

KW - miRNA

KW - noncanonical target

KW - uridylation

UR - http://www.scopus.com/inward/record.url?scp=85071345692&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2019.05.014

DO - 10.1016/j.molcel.2019.05.014

M3 - Journal article

C2 - 31178353

AN - SCOPUS:85071345692

SN - 1097-2765

VL - 75

SP - 511-522.e4

JO - Molecular Cell

JF - Molecular Cell

IS - 3

ER -