Cargando…
The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides
MicroRNAs (miRNAs) are ribonucleic acids (RNAs) of ∼21 nucleotides that interfere with the translation of messenger RNAs (mRNAs) and play significant roles in development and diseases. In bilaterian animals, the specificity of miRNA targeting is determined by sequence complementarity involving the s...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144789/ https://www.ncbi.nlm.nih.gov/pubmed/30239883 http://dx.doi.org/10.1093/nar/gky546 |
_version_ | 1783356142094647296 |
---|---|
author | Yan, Yifei Acevedo, Mariana Mignacca, Lian Desjardins, Philippe Scott, Nicolas Imane, Roqaya Quenneville, Jordan Robitaille, Julie Feghaly, Albert Gagnon, Etienne Ferbeyre, Gerardo Major, François |
author_facet | Yan, Yifei Acevedo, Mariana Mignacca, Lian Desjardins, Philippe Scott, Nicolas Imane, Roqaya Quenneville, Jordan Robitaille, Julie Feghaly, Albert Gagnon, Etienne Ferbeyre, Gerardo Major, François |
author_sort | Yan, Yifei |
collection | PubMed |
description | MicroRNAs (miRNAs) are ribonucleic acids (RNAs) of ∼21 nucleotides that interfere with the translation of messenger RNAs (mRNAs) and play significant roles in development and diseases. In bilaterian animals, the specificity of miRNA targeting is determined by sequence complementarity involving the seed. However, the role of the remaining nucleotides (non-seed) is only vaguely defined, impacting negatively on our ability to efficiently use miRNAs exogenously to control gene expression. Here, using reporter assays, we deciphered the role of the base pairs formed between the non-seed region and target mRNA. We used molecular modeling to reveal that this mechanism corresponds to the formation of base pairs mediated by ordered motions of the miRNA-induced silencing complex. Subsequently, we developed an algorithm based on this distinctive recognition to predict from sequence the levels of mRNA downregulation with high accuracy (r(2) > 0.5, P-value < 10(−12)). Overall, our discovery improves the design of miRNA-guide sequences used to simultaneously downregulate the expression of multiple predetermined target genes. |
format | Online Article Text |
id | pubmed-6144789 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-61447892018-09-25 The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides Yan, Yifei Acevedo, Mariana Mignacca, Lian Desjardins, Philippe Scott, Nicolas Imane, Roqaya Quenneville, Jordan Robitaille, Julie Feghaly, Albert Gagnon, Etienne Ferbeyre, Gerardo Major, François Nucleic Acids Res Gene regulation, Chromatin and Epigenetics MicroRNAs (miRNAs) are ribonucleic acids (RNAs) of ∼21 nucleotides that interfere with the translation of messenger RNAs (mRNAs) and play significant roles in development and diseases. In bilaterian animals, the specificity of miRNA targeting is determined by sequence complementarity involving the seed. However, the role of the remaining nucleotides (non-seed) is only vaguely defined, impacting negatively on our ability to efficiently use miRNAs exogenously to control gene expression. Here, using reporter assays, we deciphered the role of the base pairs formed between the non-seed region and target mRNA. We used molecular modeling to reveal that this mechanism corresponds to the formation of base pairs mediated by ordered motions of the miRNA-induced silencing complex. Subsequently, we developed an algorithm based on this distinctive recognition to predict from sequence the levels of mRNA downregulation with high accuracy (r(2) > 0.5, P-value < 10(−12)). Overall, our discovery improves the design of miRNA-guide sequences used to simultaneously downregulate the expression of multiple predetermined target genes. Oxford University Press 2018-09-19 2018-06-22 /pmc/articles/PMC6144789/ /pubmed/30239883 http://dx.doi.org/10.1093/nar/gky546 Text en © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Gene regulation, Chromatin and Epigenetics Yan, Yifei Acevedo, Mariana Mignacca, Lian Desjardins, Philippe Scott, Nicolas Imane, Roqaya Quenneville, Jordan Robitaille, Julie Feghaly, Albert Gagnon, Etienne Ferbeyre, Gerardo Major, François The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides |
title | The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides |
title_full | The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides |
title_fullStr | The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides |
title_full_unstemmed | The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides |
title_short | The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides |
title_sort | sequence features that define efficient and specific hago2-dependent mirna silencing guides |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144789/ https://www.ncbi.nlm.nih.gov/pubmed/30239883 http://dx.doi.org/10.1093/nar/gky546 |
work_keys_str_mv | AT yanyifei thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT acevedomariana thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT mignaccalian thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT desjardinsphilippe thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT scottnicolas thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT imaneroqaya thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT quennevillejordan thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT robitaillejulie thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT feghalyalbert thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT gagnonetienne thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT ferbeyregerardo thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT majorfrancois thesequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT yanyifei sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT acevedomariana sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT mignaccalian sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT desjardinsphilippe sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT scottnicolas sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT imaneroqaya sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT quennevillejordan sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT robitaillejulie sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT feghalyalbert sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT gagnonetienne sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT ferbeyregerardo sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides AT majorfrancois sequencefeaturesthatdefineefficientandspecifichago2dependentmirnasilencingguides |