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

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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.

Vyšlo v časopise: A Latent Pro-Survival Function for the Mir-290-295 Cluster in Mouse Embryonic Stem Cells. PLoS Genet 7(5): e32767. doi:10.1371/journal.pgen.1002054
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002054

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1. GrimsonAFarhKKJohnstonWKGarrett-EngelePLimLP 2007 MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27 91 105

2. NielsenCBShomronNSandbergRHornsteinEKitzmanJ 2007 Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. RNA 13 1894 1910

3. Ben-PorathIThomsonMWCareyVJGeRBellGW 2008 An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40 499 507

4. WernigMMeissnerAForemanRBrambrinkTKuM 2007 In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448 318 324

5. KanellopoulouCMuljoSAKungALGanesanSDrapkinR 2005 Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 19 489 501

6. MurchisonEPPartridgeJFTamOHCheloufiSHannonGJ 2005 Characterization of Dicer-deficient murine embryonic stem cells. Proc Natl Acad Sci U S A 102 12135 12140

7. LeungAGYBhutkarArjunZhengGraceXBossonAndrewDNielsenCydneyBSharpPhillipA 2010 Genome-wide identification of Ago2 binding sites from mouse embryonic stem cells with and without mature microRNAs. Nat Struct Mol Bio

8. CiaudoCServantNCognatVSarazinAKiefferE 2009 Highly dynamic and sex-specific expression of microRNAs during early ES cell differentiation. PLoS Genet 5 e1000620 doi:10.1371/journal.pgen.1000620

9. BabiarzJERubyJGWangYBartelDPBlellochR 2008 Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. Genes Dev 22 2773 2785

10. BenettiRGonzaloSJacoIMunozPGonzalezS 2008 A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat Struct Mol Biol 15 268 279

11. SinkkonenLHugenschmidtTBerningerPGaidatzisDMohnF 2008 MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nat Struct Mol Biol 15 259 267

12. WangYBaskervilleSShenoyABabiarzJEBaehnerL 2008 Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat Genet 40 1478 1483

13. HarfeBDMcManusMTMansfieldJHHornsteinETabinCJ 2005 The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc Natl Acad Sci U S A 102 10898 10903

14. CalabreseJMSharpPA 2006 Characterization of the short RNAs bound by the P19 suppressor of RNA silencing in mouse embryonic stem cells. RNA 12 2092 2102

15. LeungAKCalabreseJMSharpPA 2006 Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules. Proc Natl Acad Sci U S A 103 18125 18130

16. FriedmanRCFarhKKBurgeCBBartelDP 2009 Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19 92 105

17. LiJYuanJ 2008 Caspases in apoptosis and beyond. Oncogene 27 6194 6206

18. GuZFlemingtonCChittendenTZambettiGP 2000 ei24, a p53 response gene involved in growth suppression and apoptosis. Mol Cell Biol 20 233 241

19. ZhaoXAyerREDavisSLAmesSJFlorenceB 2005 Apoptosis factor EI24/PIG8 is a novel endoplasmic reticulum-localized Bcl-2-binding protein which is associated with suppression of breast cancer invasiveness. Cancer Res 65 2125 2129

20. TichyEDStambrookPJ 2008 DNA repair in murine embryonic stem cells and differentiated cells. Exp Cell Res 314 1929 1936

21. NitissJL 2009 Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9 338 350

22. FuldaSDebatinKM 2006 Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25 4798 4811

23. FujitaJCraneAMSouzaMKDejosezMKybaM 2008 Caspase activity mediates the differentiation of embryonic stem cells. Cell Stem Cell 2 595 601

24. UptonJPAustgenKNishinoMCoakleyKMHagenA 2008 Caspase-2 cleavage of BID is a critical apoptotic signal downstream of endoplasmic reticulum stress. Mol Cell Biol 28 3943 3951

25. TyasLBrophyVAPopeARivettAJTavareJM 2000 Rapid caspase-3 activation during apoptosis revealed using fluorescence-resonance energy transfer. EMBO Rep 1 266 270

26. NakagawaAShiYKage-NakadaiEMitaniSXueD 2010 Caspase-dependent conversion of Dicer ribonuclease into a death-promoting deoxyribonuclease. Science 328 327 334

27. BergeronLPerezGIMacdonaldGShiLSunY 1998 Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 12 1304 1314

28. KumarS 2009 Caspase 2 in apoptosis, the DNA damage response and tumour suppression: enigma no more? Nat Rev Cancer 9 897 903

29. WangYBlellochR 2009 Cell cycle regulation by MicroRNAs in embryonic stem cells. Cancer Res 69 4093 4096

30. AbbasTDuttaA 2009 p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9 400 414

31. AylonYMichaelDShmueliAYabutaNNojimaH 2006 A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization. Genes Dev 20 2687 2700

32. LiXCassidyJJReinkeCAFischboeckSCarthewRW 2009 A microRNA imparts robustness against environmental fluctuation during development. Cell 137 273 282

33. HilgersVBushatiNCohenSM 2010 Drosophila microRNAs 263a/b confer robustness during development by protecting nascent sense organs from apoptosis. PLoS Biol 8 e1000396 doi:10.1371/journal.pbio.1000396

34. HoLHTaylorRDorstynLCakourosDBouilletP 2009 A tumor suppressor function for caspase-2. Proc Natl Acad Sci U S A 106 5336 5341

35. MorkCNFallerDVSpanjaardRA 2007 Loss of putative tumor suppressor EI24/PIG8 confers resistance to etoposide. FEBS Lett 581 5440 5444

36. RippeVDittbernerLLorenzVNDrieschnerNNimzykR 2010 The two stem cell microRNA gene clusters C19MC and miR-371-3 are activated by specific chromosomal rearrangements in a subgroup of thyroid adenomas. PLoS ONE 5 e9485 doi:10.1371/journal.pone.0009485

37. LeeKHGoanYGHsiaoMLeeCHJianSH 2009 MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer. Exp Cell Res 315 2529 2538

38. PalmerRDMurrayMJSainiHKvan DongenSAbreu-GoodgerC 2010 Malignant germ cell tumors display common microRNA profiles resulting in global changes in expression of messenger RNA targets. Cancer Res 70 2911 2923

39. VoorhoevePMle SageCSchrierMGillisAJStoopH 2006 A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124 1169 1181

40. CalabreseJMSeilaACYeoGWSharpPA 2007 RNA sequence analysis defines Dicer's role in mouse embryonic stem cells. Proc Natl Acad Sci U S A 104 18097 18102

41. DoenchJGSharpPA 2004 Specificity of microRNA target selection in translational repression. Genes Dev 18 504 511

42. SeilaACCalabreseJMLevineSSYeoGWRahlPB 2008 Divergent transcription from active promoters. Science 322 1849 1851