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A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells

MicroRNAs (miRNAs) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. Here we describe such a role for the mir-2...

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Autores principales: Zheng, Grace X. Y., Ravi, Arvind, Calabrese, J. Mauro, Medeiros, Lea A., Kirak, Oktay, Dennis, Lucas M., Jaenisch, Rudolf, Burge, Christopher B., Sharp, Phillip A.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088722/
https://www.ncbi.nlm.nih.gov/pubmed/21573140
http://dx.doi.org/10.1371/journal.pgen.1002054
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author Zheng, Grace X. Y.
Ravi, Arvind
Calabrese, J. Mauro
Medeiros, Lea A.
Kirak, Oktay
Dennis, Lucas M.
Jaenisch, Rudolf
Burge, Christopher B.
Sharp, Phillip A.
author_facet Zheng, Grace X. Y.
Ravi, Arvind
Calabrese, J. Mauro
Medeiros, Lea A.
Kirak, Oktay
Dennis, Lucas M.
Jaenisch, Rudolf
Burge, Christopher B.
Sharp, Phillip A.
author_sort Zheng, Grace X. Y.
collection PubMed
description MicroRNAs (miRNAs) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. Here we describe such a role for the mir-290-295 cluster, the dominant miRNA cluster in mouse embryonic stem cells (mESCs). Examination of a target list generated from bioinformatic prediction, as well as expression data following miRNA loss, revealed strong enrichment for apoptotic regulators, two of which we validated directly: Caspase 2, the most highly conserved mammalian caspase, and Ei24, a p53 transcriptional target. Consistent with these predictions, mESCs lacking miRNAs were more likely to initiate apoptosis following genotoxic exposure to gamma irradiation or doxorubicin. Knockdown of either candidate partially rescued this pro-apoptotic phenotype, as did transfection of members of the mir-290-295 cluster. These findings were recapitulated in a specific mir-290-295 deletion line, confirming that they reflect miRNA functions at physiological levels. In contrast to the basal regulatory roles previously identified, the pro-survival phenotype shown here may be most relevant to stressful gestations, where pro-oxidant metabolic states induce DNA damage. Similarly, this cluster may mediate chemotherapeutic resistance in a neoplastic context, making it a useful clinical target.
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spelling pubmed-30887222011-05-13 A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells Zheng, Grace X. Y. Ravi, Arvind Calabrese, J. Mauro Medeiros, Lea A. Kirak, Oktay Dennis, Lucas M. Jaenisch, Rudolf Burge, Christopher B. Sharp, Phillip A. PLoS Genet Research Article MicroRNAs (miRNAs) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. Here we describe such a role for the mir-290-295 cluster, the dominant miRNA cluster in mouse embryonic stem cells (mESCs). Examination of a target list generated from bioinformatic prediction, as well as expression data following miRNA loss, revealed strong enrichment for apoptotic regulators, two of which we validated directly: Caspase 2, the most highly conserved mammalian caspase, and Ei24, a p53 transcriptional target. Consistent with these predictions, mESCs lacking miRNAs were more likely to initiate apoptosis following genotoxic exposure to gamma irradiation or doxorubicin. Knockdown of either candidate partially rescued this pro-apoptotic phenotype, as did transfection of members of the mir-290-295 cluster. These findings were recapitulated in a specific mir-290-295 deletion line, confirming that they reflect miRNA functions at physiological levels. In contrast to the basal regulatory roles previously identified, the pro-survival phenotype shown here may be most relevant to stressful gestations, where pro-oxidant metabolic states induce DNA damage. Similarly, this cluster may mediate chemotherapeutic resistance in a neoplastic context, making it a useful clinical target. Public Library of Science 2011-05-05 /pmc/articles/PMC3088722/ /pubmed/21573140 http://dx.doi.org/10.1371/journal.pgen.1002054 Text en Zheng 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zheng, Grace X. Y.
Ravi, Arvind
Calabrese, J. Mauro
Medeiros, Lea A.
Kirak, Oktay
Dennis, Lucas M.
Jaenisch, Rudolf
Burge, Christopher B.
Sharp, Phillip A.
A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells
title A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells
title_full A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells
title_fullStr A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells
title_full_unstemmed A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells
title_short A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells
title_sort latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088722/
https://www.ncbi.nlm.nih.gov/pubmed/21573140
http://dx.doi.org/10.1371/journal.pgen.1002054
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