title: A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells.
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.
authors.affiliation: MIT Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
authors.forename: Grace X Y
authors.initials: GX
authors.lastname: Zheng
authors.forename: Arvind
authors.initials: A
authors.lastname: Ravi
authors.forename: J Mauro
authors.initials: JM
authors.lastname: Calabrese
authors.forename: Lea A
authors.initials: LA
authors.lastname: Medeiros
authors.forename: Oktay
authors.initials: O
authors.lastname: Kirak
authors.forename: Lucas M
authors.initials: LM
authors.lastname: Dennis
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Burge
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Sharp
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D005720:Gamma Rays; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C526185:EI24 protein, mouse; D035683:MicroRNAs; D009687:Nuclear Proteins; D004317:Doxorubicin; D053143:Caspase 2