mi-IsoNet: systems-scale microRNA landscape reveals rampant isoform-mediated gain of target interaction diversity and signaling specificity.
Cluster Analysis
Computational Biology
/ methods
Gene Expression Profiling
/ methods
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Genetic Variation
High-Throughput Nucleotide Sequencing
/ methods
Humans
MicroRNAs
/ genetics
Neoplasms
/ genetics
RNA Isoforms
/ genetics
RNA, Messenger
/ genetics
Signal Transduction
/ genetics
Survival Analysis
functional diversity
gain of interactions
gene regulatory networks
isoforms
microRNA (miRNA)
signaling specificity
Journal
Briefings in bioinformatics
ISSN: 1477-4054
Titre abrégé: Brief Bioinform
Pays: England
ID NLM: 100912837
Informations de publication
Date de publication:
02 09 2021
02 09 2021
Historique:
received:
21
07
2020
revised:
27
02
2021
accepted:
01
03
2021
pubmed:
16
4
2021
medline:
23
11
2021
entrez:
15
4
2021
Statut:
ppublish
Résumé
MicroRNA (miRNA) is not a single sequence, but a series of multiple variants (also termed isomiRs) with sequence and expression heterogeneity. Whether and how these isoforms contribute to functional variation and complexity at the systems and network levels remain largely unknown. To explore this question systematically, we comprehensively analyzed the expression of small RNAs and their target sites to interrogate functional variations between novel isomiRs and their canonical miRNA sequences. Our analyses of the pan-cancer landscape of miRNA expression indicate that multiple isomiRs generated from the same miRNA locus often exhibit remarkable variation in their sequence, expression and function. We interrogated abundant and differentially expressed 5' isomiRs with novel seed sequences via seed shifting and identified many potential novel targets of these 5' isomiRs that would expand interaction capabilities between small RNAs and mRNAs, rewiring regulatory networks and increasing signaling circuit complexity. Further analyses revealed that some miRNA loci might generate diverse dominant isomiRs that often involved isomiRs with varied seeds and arm-switching, suggesting a selective advantage of multiple isomiRs in regulating gene expression. Finally, experimental validation indicated that isomiRs with shifted seed sequences could regulate novel target mRNAs and therefore contribute to regulatory network rewiring. Our analysis uncovers a widespread expansion of isomiR and mRNA interaction networks compared with those seen in canonical small RNA analysis; this expansion suggests global gene regulation network perturbations by alternative small RNA variants or isoforms. Taken together, the variations in isomiRs that occur during miRNA processing and maturation are likely to play a far more complex and plastic role in gene regulation than previously anticipated.
Identifiants
pubmed: 33855356
pii: 6225086
doi: 10.1093/bib/bbab091
pmc: PMC8579161
pii:
doi:
Substances chimiques
MicroRNAs
0
RNA Isoforms
0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : U01 CA217842
Pays : United States
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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