We have performed the first extensive profiling of Epstein-Barr virus (EBV) miRNAs on in vivo derived normal and neoplastic infected tissues. We describe a unique pattern of viral miRNA expression by normal infected cells in vivo expressing restricted viral latency programs (germinal center: Latency II and memory B: Latency I/0). This includes the complete absence of 15 of the 34 miRNAs profiled. These consist of 12 BART miRNAs (including approximately half of Cluster 2) and 3 of the 4 BHRF1 miRNAs. All but 2 of these absent miRNAs become expressed during EBV driven growth (Latency III). Furthermore, EBV driven growth is accompanied by a 5–10 fold down regulation in the level of the BART miRNAs expressed in germinal center and memory B cells. Therefore, Latency III also expresses a unique pattern of viral miRNAs. We refer to the miRNAs that are specifically expressed in EBV driven growth as the Latency III associated miRNAs. In EBV associated tumors that employ Latency I or II (Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and gastric carcinoma), the Latency III associated BART but not BHRF1 miRNAs are up regulated. Thus BART miRNA expression is deregulated in the EBV associated tumors. This is the first demonstration that Latency III specific genes (the Latency III associated BARTs) can be expressed in these tumors. The EBV associated tumors demonstrate very similar patterns of miRNA expression yet were readily distinguished when the expression data were analyzed either by heat-map/clustering or principal component analysis. Systematic analysis revealed that the information distinguishing the tumor types was redundant and distributed across all the miRNAs. This resembles “secret sharing” algorithms where information can be distributed among a large number of recipients in such a way that any combination of a small number of recipients is able to understand the message. Biologically, this may be a consequence of functional redundancy between the miRNAs.
Vyšlo v časopise: A Novel Persistence Associated EBV miRNA Expression Profile Is Disrupted in Neoplasia. PLoS Pathog 7(8): e32767. doi:10.1371/journal.ppat.1002193 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002193
1. RickinsonABKieffE 2007 Epstein-Barr Virus. KnipeDMHowleyPM Virology. 5th ed New York Lippincott Williams and Wilkins 2655 2700
2. Thorley-LawsonD 2005 EBV persistence and latent infection in vivo. ESRHowleyPM Epstein-Barr Virus. 1st ed Norfolk, England Caister Academic Press 309 349
3. Thorley-LawsonDAAlldayMJ 2008 The curious case of the tumour virus: 50 years of Burkitt's lymphoma. Nat Rev Microbiol 6 913 924
4. KieffERickinsonAB 2007 Epstein-Barr Virus and Its Replication. KnipeDMHowleyPM Fields Virology 5th ed Philadelphia Lippincott Williams & Wilkins 2603 2654
5. RoughanJEThorley-LawsonDA 2009 The intersection of Epstein-Barr virus with the germinal center. J Virol 83 3968 3976
6. RoughanJETorgborCThorley-LawsonDA 2010 Germinal center B cells latently infected with Epstein-Barr virus proliferate extensively but do not increase in number. J Virol 84 1158 1168
7. Thorley-LawsonDAGrossA 2004 Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 350 1328 1337
8. BartelDP 2004 MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116 281 297
9. CullenBR 2006 Viruses and microRNAs. Nat Genet 38 Suppl S25 30
10. CaiXSchaferALuSBilelloJPDesrosiersRC 2006 Epstein-Barr virus microRNAs are evolutionarily conserved and differentially expressed. PLoS Pathog 2 e23
11. ChenSJChenGHChenYHLiuCYChangKP 2010 Characterization of Epstein-Barr virus miRNAome in nasopharyngeal carcinoma by deep sequencing. PLoS One 5 In press
12. HadinotoVShapiroMGreenoughTCSullivanJLLuzuriagaK 2008 On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood 111 1420 1427
13. PfefferSZavolanMGrasserFAChienMRussoJJ 2004 Identification of virus-encoded microRNAs. Science 304 734 736
14. Al-MozainiMBodelonGKarsteglCEJinBAl-AhdalM 2009 Epstein-Barr virus BART gene expression. J Gen Virol 90 307 316
15. AmorosoRFitzsimmonsLThomasWAKellyGLRoweM 2011 Quantitative studies of Epstein-Barr virus-encoded microRNAs provide novel insights into their regulation. J Virol 85 996 1010
16. CosmopoulosKPegtelMHawkinsJMoffettHNovinaC 2009 Comprehensive profiling of Epstein-Barr virus microRNAs in nasopharyngeal carcinoma. J Virol 83 2357 2367
17. ImigJMotschNZhuJYBarthSOkoniewskiM 2011 microRNA profiling in Epstein-Barr virus-associated B-cell lymphoma. Nucleic Acids Res 39 1880 1893
18. PrattZLKuzembayevaMSenguptaSSugdenB 2009 The microRNAs of Epstein-Barr Virus are expressed at dramatically differing levels among cell lines. Virology 386 387 397
19. GibcusJHTanLPHarmsGSchakelRNde JongD 2009 Hodgkin lymphoma cell lines are characterized by a specific miRNA expression profile. Neoplasia 11 167 176
20. LawrieCHChiJTaylorSTramontiDBallabioE 2009 Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma. J Cell Mol Med 13 1248 1260
21. LiangYRidzonDWongLChenC 2007 Characterization of microRNA expression profiles in normal human tissues. BMC Genomics 8 166
22. MalumbresRSarosiekKACubedoERuizJWJiangX 2009 Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas. Blood 113 3754 3764
23. Van VlierberghePDe WeerAMestdaghPFeysTDe PreterK 2009 Comparison of miRNA profiles of microdissected Hodgkin/Reed-Sternberg cells and Hodgkin cell lines versus CD77+ B-cells reveals a distinct subset of differentially expressed miRNAs. Br J Haematol 147 686 690
24. ZhangJJimaDDJacobsCFischerRGottweinE 2009 Patterns of microRNA expression characterize stages of human B-cell differentiation. Blood 113 4586 4594
25. FeederleRLinnstaedtSDBannertHLipsHBencunM 2011 A Viral microRNA Cluster Strongly Potentiates the Transforming Properties of a Human Herpesvirus. PLoS Pathog 7 In press
26. SetoEMoosmannAGrommingerSWalzNGrundhoffA 2010 Micro RNAs of Epstein-Barr virus promote cell cycle progression and prevent apoptosis of primary human B cells. PLoS Pathog 6 e1001063
27. XingLKieffE 2007 Epstein-Barr Virus BHRF1 Micro - and Stable RNAs during Latency III and after Induction of Replication. J Virol 81 9967 9975
28. XiaTO'HaraAAraujoIBarretoJCarvalhoE 2008 EBV microRNAs in primary lymphomas and targeting of CXCL-11 by ebv-mir-BHRF1-3. Cancer Res 68 1436 1442
29. BarthSPfuhlTMamianiAEhsesCRoemerK 2008 Epstein-Barr virus-encoded microRNA miR-BART2 down-regulates the viral DNA polymerase BALF5. Nucleic Acids Res 36 666 675
30. LoAKToKFLoKWLungRWHuiJW 2007 Modulation of LMP1 protein expression by EBV-encoded microRNAs. Proc Natl Acad Sci U S A 104 16164 16169
31. LungRWTongJHSungYMLeungPSNgDC 2009 Modulation of LMP2A expression by a newly identified Epstein-Barr virus-encoded microRNA miR-BART22. Neoplasia 11 1174 1184
32. ChoyEYSiuKLKokKHLungRWTsangCM 2008 An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. J Exp Med 205 2551 2560
33. MarquitzARMathurANamCSRaab-TraubN 2011 The Epstein-Barr Virus BART microRNAs target the pro-apoptotic protein Bim. Virology 412 392 400
34. NachmaniDStern-GinossarNSaridRMandelboimO 2009 Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe 5 376 385
35. RobertsonESTomkinsonBKieffE 1994 An Epstein-Barr virus with a 58-kilobase-pair deletion that includes BARF0 transforms B lymphocytes in vitro. J Virol 68 1449 1458
36. CaldwellRGWilsonJBAndersonSJLongneckerR 1998 Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9 405 411
37. LongneckerRMillerCLMiaoXQTomkinsonBKieffE 1993 The last seven transmembrane and carboxy-terminal cytoplasmic domains of Epstein-Barr virus latent membrane protein 2 (LMP2) are dispensable for lymphocyte infection and growth transformation in vitro. J Virol 67 2006 2013
38. BlakelyeGR 1979 Safeguarding cryptographic keys. Proc Nat Comp Conf 48 313 317
39. ShamirA 1979 How to share a secret. Commun ACM 22 612 613
40. LaichalkLLHochbergDBabcockGJFreemanRBThorley-LawsonDA 2002 The dispersal of mucosal memory B cells: evidence from persistent EBV infection. Immunity 16 745 754
41. MarquitzARMathurANamCSRaab-TraubN 2011 The Epstein-Barr Virus BART microRNAs target the pro-apoptotic protein Bim. Virology 412 392 400
42. EdwardsRHMarquitzARRaab-TraubN 2008 Epstein-Barr virus BART microRNAs are produced from a large intron prior to splicing. J Virol 82 9094 9106
43. CheungHHDavisAJLeeTLPangALNagraniS 2011 Methylation of an intronic region regulates miR-199a in testicular tumor malignancy. Oncogene In press
44. DattaJKutayHNasserMWNuovoGJWangB 2008 Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 68 5049 5058
45. HanLWitmerPDCaseyEValleDSukumarS 2007 DNA methylation regulates MicroRNA expression. Cancer Biol Ther 6 1284 1288
46. IizasaHWulffBEAllaNRMaragkakisMMegrawM 2010 Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency. J Biol Chem 285 33358 33370
47. KimDNSongYJLeeSK 2011 The Role of Promoter Methylation in Epstein-Barr Virus MicroRNA Expression in EBV-infected B cell lines. Exp Mol Med In press
48. ChatterjeeSFaslerMBussingIGrosshansH 2011 Target-mediated protection of endogenous microRNAs in C. elegans. Dev Cell 20 388 396
49. AbbottALAlvarez-SaavedraEMiskaEALauNCBartelDP 2005 The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans. Dev Cell 9 403 414
50. AllenRSLiJStahleMIDubroueAGublerF 2007 Genetic analysis reveals functional redundancy and the major target genes of the Arabidopsis miR159 family. Proc Natl Acad Sci U S A 104 16371 16376
51. IwamaHMuraoKImachiHIshidaT 2011 MicroRNA networks alter to conform to transcription factor networks adding redundancy and reducing the repertoire of target genes for coordinated regulation. Mol Biol Evol 28 639 646
52. SieberPWellmerFGheyselinckJRiechmannJLMeyerowitzEM 2007 Redundancy and specialization among plant microRNAs: role of the MIR164 family in developmental robustness. Development 134 1051 1060
53. Kim doNChaeHSOhSTKangJHParkCH 2007 Expression of viral microRNAs in Epstein-Barr virus-associated gastric carcinoma. J Virol 81 1033 1036
54. ChenMRMiddeldorpJMHaywardSD 1993 Separation of the complex DNA binding domain of EBNA-1 into DNA recognition and dimerization subdomains of novel structure. J Virol 67 4875 4885
55. MeijPVervoortMBMeijerCJBloemenaEMiddeldorpJM 2000 Production monitoring and purification of EBV encoded latent membrane protein 1 expressed and secreted by recombinant baculovirus infected insect cells. J Virol Methods 90 193 204
56. SouzaTAStollarBDSullivanJLLuzuriagaKThorley-LawsonDA 2007 Influence of EBV on the peripheral blood memory B cell compartment. J Immunol 179 3153 3160
57. HutzingerRFeederleRMrazekJSchiefermeierNBalwierzPJ 2009 Expression and processing of a small nucleolar RNA from the Epstein-Barr virus genome. PLoS Pathog 5 e1000547
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
