The AGO2 adaptor LIMD1 expands the functional and evolutionary reach of microRNA targeting

MicroRNA (miRNA) silencing is classically ascribed to RNA-sequence rules that guide Argonaute 2 (AGO2) targeting. Using chimeric eCLIP and complementary analyses in CRISPR-edited human lung epithelial cells, we show that efficient miRNA targeting also depends on the AGO2 adaptor-scaffold LIMD1. In LIMD1-deficient cells, AGO2 binds more miRNAs, but each AGO2-miRNA engages fewer transcripts and sites, reducing occupancy and halving both the breadth and depth of targeting. LIMD1 dependence is most pronounced for poorly conserved, weakly seed-paired sites that nonetheless form stable duplexes. LIMD1 deficiency alters AGO2 footprints and derepresses oncogenic targets inversely correlated with LIMD1 expression in lung adenocarcinoma. Thus, LIMD1 modifies the outcome of sequence-defined interactions that would otherwise be infrequent, unstable, or unproductive, revealing an adaptor-governed layer of posttranscriptional regulation beyond RNA-sequence rules.

Authors

Institutions

Publication Details

Journal
Science Advances
Published
2026-07-23
DOI
https://doi.org/10.1126/sciadv.aed6875
Primary Topic
MicroRNA in disease regulation
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

The AGO2 adaptor LIMD1 expands the functional and evolutionary reach of microRNA targeting

Eleni Maniati, Sam Griffiths‐Jones, Faraz K. Mardakheh, Kunal Shah et al.
Science Advances
MicroRNA in disease regulation
article

The AGO2 adaptor LIMD1 expands the functional and evolutionary reach of microRNA targeting

Eleni Maniati, Sam Griffiths‐Jones, Faraz K. Mardakheh, Kunal Shah, Antonio De Marco, Tyson V. Sharp, Alex Crozier, Pedro R. Cutillas, Vinothini Rajeeve, Kylie A. Shen, Dimitris Lagos, Paul Grevitt, Jun Wang, Anisha Thind, Diana Cox
article en

Abstract

MicroRNA (miRNA) silencing is classically ascribed to RNA-sequence rules that guide Argonaute 2 (AGO2) targeting. Using chimeric eCLIP and complementary analyses in CRISPR-edited human lung epithelial cells, we show that efficient miRNA targeting also depends on the AGO2 adaptor-scaffold LIMD1. In LIMD1-deficient cells, AGO2 binds more miRNAs, but each AGO2-miRNA engages fewer transcripts and sites, reducing occupancy and halving both the breadth and depth of targeting. LIMD1 dependence is most pronounced for poorly conserved, weakly seed-paired sites that nonetheless form stable duplexes. LIMD1 deficiency alters AGO2 footprints and derepresses oncogenic targets inversely correlated with LIMD1 expression in lung adenocarcinoma. Thus, LIMD1 modifies the outcome of sequence-defined interactions that would otherwise be infrequent, unstable, or unproductive, revealing an adaptor-governed layer of posttranscriptional regulation beyond RNA-sequence rules.

Science AdvancesVol. 12(30)
University of Essex (GB), Queen Mary University of London (GB), University of Manchester (GB), University of Oxford (GB), Eclipse Bioinnovations (United States) (US), University of York (GB)
Barts Charity, Cancer Research UK, City, University of London, Medical Research Council, Biotechnology and Biological Sciences Research Council
Openalex Percentile: Top 12%
MicroRNA in disease regulation
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.