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Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors

Post-transcriptional regulation is regarded as one of the major processes involved in the regulation of gene expression. It is mainly performed by RNA binding proteins and microRNAs, which target RNAs and typically affect their stability. Recent efforts from the scientific community have aimed at un...

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Autores principales: Plass, Mireya, Rasmussen, Simon H., Krogh, Anders
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409497/
https://www.ncbi.nlm.nih.gov/pubmed/28410363
http://dx.doi.org/10.1371/journal.pcbi.1005460
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author Plass, Mireya
Rasmussen, Simon H.
Krogh, Anders
author_facet Plass, Mireya
Rasmussen, Simon H.
Krogh, Anders
author_sort Plass, Mireya
collection PubMed
description Post-transcriptional regulation is regarded as one of the major processes involved in the regulation of gene expression. It is mainly performed by RNA binding proteins and microRNAs, which target RNAs and typically affect their stability. Recent efforts from the scientific community have aimed at understanding post-transcriptional regulation at a global scale by using high-throughput sequencing techniques such as cross-linking and immunoprecipitation (CLIP), which facilitates identification of binding sites of these regulatory factors. However, the diversity in the experimental procedures and bioinformatics analyses has hindered the integration of multiple datasets and thus limited the development of an integrated view of post-transcriptional regulation. In this work, we have performed a comprehensive analysis of 107 CLIP datasets from 49 different RBPs in HEK293 cells to shed light on the complex interactions that govern post-transcriptional regulation. By developing a more stringent CLIP analysis pipeline we have discovered the existence of conserved regulatory AU-rich regions in the 3’UTRs where miRNAs and RBPs that regulate several processes such as polyadenylation or mRNA stability bind. Analogous to promoters, many factors have binding sites overlapping or in close proximity in these hotspots and hence the regulation of the mRNA may depend on their relative concentrations. This hypothesis is supported by RBP knockdown experiments that alter the relative concentration of RBPs in the cell. Upon AGO2 knockdown (KD), transcripts containing “free” target sites show increased expression levels compared to those containing target sites in hotspots, which suggests that target sites within hotspots are less available for miRNAs to bind. Interestingly, these hotspots appear enriched in genes with regulatory functions such as DNA binding and RNA binding. Taken together, our results suggest that hotspots are functional regulatory elements that define an extra layer of regulation of post-transcriptional regulatory networks.
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spelling pubmed-54094972017-05-14 Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors Plass, Mireya Rasmussen, Simon H. Krogh, Anders PLoS Comput Biol Research Article Post-transcriptional regulation is regarded as one of the major processes involved in the regulation of gene expression. It is mainly performed by RNA binding proteins and microRNAs, which target RNAs and typically affect their stability. Recent efforts from the scientific community have aimed at understanding post-transcriptional regulation at a global scale by using high-throughput sequencing techniques such as cross-linking and immunoprecipitation (CLIP), which facilitates identification of binding sites of these regulatory factors. However, the diversity in the experimental procedures and bioinformatics analyses has hindered the integration of multiple datasets and thus limited the development of an integrated view of post-transcriptional regulation. In this work, we have performed a comprehensive analysis of 107 CLIP datasets from 49 different RBPs in HEK293 cells to shed light on the complex interactions that govern post-transcriptional regulation. By developing a more stringent CLIP analysis pipeline we have discovered the existence of conserved regulatory AU-rich regions in the 3’UTRs where miRNAs and RBPs that regulate several processes such as polyadenylation or mRNA stability bind. Analogous to promoters, many factors have binding sites overlapping or in close proximity in these hotspots and hence the regulation of the mRNA may depend on their relative concentrations. This hypothesis is supported by RBP knockdown experiments that alter the relative concentration of RBPs in the cell. Upon AGO2 knockdown (KD), transcripts containing “free” target sites show increased expression levels compared to those containing target sites in hotspots, which suggests that target sites within hotspots are less available for miRNAs to bind. Interestingly, these hotspots appear enriched in genes with regulatory functions such as DNA binding and RNA binding. Taken together, our results suggest that hotspots are functional regulatory elements that define an extra layer of regulation of post-transcriptional regulatory networks. Public Library of Science 2017-04-14 /pmc/articles/PMC5409497/ /pubmed/28410363 http://dx.doi.org/10.1371/journal.pcbi.1005460 Text en © 2017 Plass et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Plass, Mireya
Rasmussen, Simon H.
Krogh, Anders
Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors
title Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors
title_full Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors
title_fullStr Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors
title_full_unstemmed Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors
title_short Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors
title_sort highly accessible au-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409497/
https://www.ncbi.nlm.nih.gov/pubmed/28410363
http://dx.doi.org/10.1371/journal.pcbi.1005460
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