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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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2011
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| Online Access: | http://hdl.handle.net/1721.1/64961 https://orcid.org/0000-0003-1465-1691 |
| _version_ | 1826217554804211712 |
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| author | Ravi, Arvind Calabrese, J. Mauro Medeiros, Lea Ann Kirak, Oktay Dennis, Lucas M. Jaenisch, Rudolf Sharp, Phillip A. Zheng, Xinying Grace Burge, Christopher B |
| author2 | Whitaker College of Health Sciences and Technology |
| author_facet | Whitaker College of Health Sciences and Technology Ravi, Arvind Calabrese, J. Mauro Medeiros, Lea Ann Kirak, Oktay Dennis, Lucas M. Jaenisch, Rudolf Sharp, Phillip A. Zheng, Xinying Grace Burge, Christopher B |
| author_sort | Ravi, Arvind |
| collection | MIT |
| 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. |
| first_indexed | 2024-09-23T17:05:31Z |
| format | Article |
| id | mit-1721.1/64961 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:05:31Z |
| publishDate | 2011 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/649612022-10-03T10:20:13Z A Latent Pro-survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells Ravi, Arvind Calabrese, J. Mauro Medeiros, Lea Ann Kirak, Oktay Dennis, Lucas M. Jaenisch, Rudolf Sharp, Phillip A. Zheng, Xinying Grace Burge, Christopher B Whitaker College of Health Sciences and Technology Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Computational and Systems Biology Program Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Burge, Christopher B. Zheng, Grace X. Y. Ravi, Arvind Calabrese, J. Mauro Medeiros, Lea Ann Dennis, Lucas M. Jaenisch, Rudolf Burge, Christopher B. Sharp, Phillip A. 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. National Institutes of Health (U.S.) (NIH grant RO1-GM34277) National Cancer Institute (U.S.) (NCI grant PO1-CA42063) National Cancer Institute (U.S.) (NCI Cancer Center Support (core) grant P30-CA14051) 2011-07-28T14:14:13Z 2011-07-28T14:14:13Z 2011-05 2011-01 Article http://purl.org/eprint/type/JournalArticle 1553-7404 1553-7390 http://hdl.handle.net/1721.1/64961 Zheng, Grace X. Y. et al. “A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells.” Ed. Michael T. McManus. PLoS Genetics 7.5 (2011) : e1002054. https://orcid.org/0000-0003-1465-1691 en_US http://dx.doi.org/10.1371/journal.pgen.1002054 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Ravi, Arvind Calabrese, J. Mauro Medeiros, Lea Ann Kirak, Oktay Dennis, Lucas M. Jaenisch, Rudolf Sharp, Phillip A. Zheng, Xinying Grace Burge, Christopher B 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 |
| url | http://hdl.handle.net/1721.1/64961 https://orcid.org/0000-0003-1465-1691 |
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