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

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

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dc.contributor.author Zheng, Grace X. Y.
dc.contributor.author Medeiros, Lea A.
dc.contributor.author Kirak, Oktay
dc.contributor.author Dennis, Lucas M.
dc.contributor.author Jaenisch, Rudolf
dc.contributor.author Burge, Christopher B.
dc.contributor.author Ravi, Arvind
dc.contributor.author Calabrese, Joseph Michael
dc.contributor.author McManus, Michael Louis
dc.contributor.author Sharp, Phillip A.
dc.date.accessioned 2012-01-03T04:08:15Z
dc.date.issued 2011
dc.identifier.citation Zheng, Grace X. Y., Arvind Ravi, J. Mauro Calabrese, Lea A. Medeiros, Oktay Kirak, Lucas M. Dennis, Rudolf Jaenisch, Christopher B. Burge, and Phillip A. Sharp. 2011. A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells. PLoS Genetics 7(5): e1002054. en_US
dc.identifier.issn 1553-7390 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5978751
dc.description.abstract 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. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi://10.1371/journal.pgen.1002054 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088722/pdf/ en_US
dash.license LAA
dc.subject biology en_US
dc.subject computational biology en_US
dc.subject genomics en_US
dc.subject functional genomics en_US
dc.subject microarrays en_US
dc.subject sequence analysis en_US
dc.subject signaling networks en_US
dc.subject molecular cell biology en_US
dc.subject gene expression en_US
dc.subject RNA interference en_US
dc.subject nucleic acids en_US
dc.subject RNA en_US
dc.subject cell death en_US
dc.subject cell growth en_US
dc.subject cellular stress responses en_US
dc.title A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS Genetics en_US
dash.depositing.author McManus, Michael Louis
dc.date.available 2012-01-03T04:08:15Z
dash.affiliation.other 103041 en_US
dash.affiliation.other 103037 en_US

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