Viral MicroRNA Targetome of KSHV-Infected Primary Effusion Lymphoma Cell Lines

Gottwein, Eva; Corcoran, David L.; Mukherjee, Neelanjan; Skalsky, Rebecca L.; Hafner, Markus; Nusbaum, Jeffrey D.; Shamulailatpam, Priscilla; Love, Cassandra; Davé, Sandeep S.; Tuschl, Thomas; Ohler, Uwe; Cullen, Bryan R.

doi:10.1016/j.chom.2011.09.012

Cited by 272 publications

(450 citation statements)

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“…IPA was able to map 29,870, 7,612, and 7,288 genes from these datasets, suggesting that 25.5% of all IPA recognized genes were down-regulated and 24.4% were up-regulated to some degree. The compare analysis function of IPA was used to overlap the 7,612 and 7,288 genes with those genes targeted by EBV miRNA in the PEL PAR-CLIP data [downloaded from the supplementary data in the report by Gottwein et al (28)] or from bioinformatically generated target lists from Targetscan or Diana-microT, algorithms which are available as online tools. The actual overlap in these gene sets was compared with the null hypothesis overlap (25.5% or 24.4% of each list) using a χ 2 analysis.…”

Section: Methodsmentioning

confidence: 99%

“…There were 9,187 spots significantly down-regulated to any amount with a false discovery rate (FDR) of less than 0.05 on the microarray. The most comprehensive list of BART miRNA targets has been determined using a technique known as photoactivatable-ribonucleoside enhanced crosslinking and immunoprecipitation (PAR-CLIP), where miRNA targets from a dual Karposi's sarcoma-associated herpesvirus (KSHV)/EBVinfected primary effusion lymphoma cell line were immunoprecipitated and sequenced (28). Of the 2,764 unique mRNAs bound to EBV BART miRNAs, 940 were also down-regulated in the infected AGS cells Dataset S1).…”

Section: Genes With Decreased Expression Are Enriched In Bart Mirnamentioning

confidence: 99%

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Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression

Marquitz

Mathur

Shair

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Latent infection of EBV is linked to the development of multiple cancers that have distinct patterns of expression of viral proteins and microRNAs (miRNAs). In this study, we show that in vitro infection of a gastric epithelial cell line with EBV alters growth properties and induces growth in soft agar. The infected cells have high levels of expression of a large cluster of viral miRNAs, [the BamHI A rightward transcript (BART) miRNAs] and limited viral protein expression. Expression profile microarray analysis of this cell line revealed a large number of changes in cellular expression, with decreased expression of many genes. Inhibition of the traceexpressed levels of the viral oncoprotein, latent membrane protein 1, did not affect growth or alter the pattern of cellular expression. The expression changes are highly enriched for genes involved in cell motility and transformation pathways, suggesting these changes are important for the altered growth phenotype. Importantly, the transcripts decreased by microarray are significantly enriched in both experimentally and bioinformatically predicted BART miRNA targets. The absence of viral protein expression and the enrichment for viral miRNA targets in the modulated cell genes suggest that the BART miRNAs are major contributors to the transformed growth properties of the EBV-infected cells. The ability to affect cell growth through miRNA expression without viral protein expression would be a major factor in the development of cancer in individuals with functional immune systems.gastric carcinoma | oncogenesis | herpes virus

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Section: Methodsmentioning

confidence: 99%

Section: Genes With Decreased Expression Are Enriched In Bart Mirnamentioning

confidence: 99%

Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression

Marquitz

Mathur

Shair

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The CLIP-based techniques and their variants have been extensively used during the last few years to map the RNA targets and binding sites of several RBPs in human and murine cell lines and tissues. This includes miRISC components (48,52,53) , the Pumilio and FBF [Fem-3 binding factor] (PUF) domain family member Pumilio-2 (PUM2), the insulin-like growth factor 2 mRBPs 1, 2, and 3 (IGF2BP1-3), Quaking (QKI) (48) , heterogeneous nuclear ribonucleoprotein (hnRNP) particles (47) , T-cell intracellular antigen 1 (TIA1) and the related TIA1-like 1 (TIAL1) protein (54) , the splicing regulators TAR DNA binding protein 43 (TDP-43) (55) , Nova-1 and Nova-2 (43,56) , fragile X mental retardation protein (FMRP) (57) , the FET family proteins fused in sarcoma (FUS), Ewing sarcoma breakpoint region 1 (EWSR1) and TATA box binding protein (TBP)-associated factor 15 (TAF15) (58) , and human antigen R (HuR) (59,60) . Furthermore, PAR-CLIP has been applied in worms (61) and yeast (62) .…”

Section: Ribonomics -Global Methods For the Identifi Cation Of Rna-prmentioning

confidence: 99%

RNA regulons and the RNA-protein interaction network

Imig¹,

Kanitz²,

Gerber

2012

BioMolecular Concepts

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The development of genome-wide analysis tools has prompted global investigation of the gene expression program, revealing highly coordinated control mechanisms that ensure proper spatiotemporal activity of a cell ' s macromolecular components. With respect to the regulation of RNA transcripts, the concept of RNA regulons, which -by analogy with DNA regulons in bacteria -refers to the coordinated control of functionally related RNA molecules, has emerged as a unifying theory that describes the logic of regulatory RNA-protein interactions in eukaryotes. Hundreds of RNA-binding proteins and small non-coding RNAs, such as microRNAs, bind to distinct elements in target RNAs, thereby exerting specifi c and concerted control over posttranscriptional events. In this review, we discuss recent reports committed to systematically explore the RNA-protein interaction network and outline some of the principles and recurring features of RNA regulons: the coordination of functionally related mRNAs through RNAbinding proteins or non-coding RNAs, the modular structure of its components, and the dynamic rewiring of RNA-protein interactions upon exposure to internal or external stimuli. We also summarize evidence for robust combinatorial control of mRNAs, which could determine the ultimate fate of each mRNA molecule in a cell. Finally, the compilation and integration of global protein-RNA interaction data has yielded fi rst insights into network structures and provided the hypothesis that RNA regulons may, in part, constitute noise ' buffers ' to handle stochasticity in cellular transcription.

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“…Indeed, analysis of RISC-bound RNA targets in cells transfected with either a synthetic miR-155, miR-K11, or miR-92a miRNA duplex, using the previously described photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation technique (PAR-CLIP) (Hafner et al 2010;Gottwein et al 2011), revealed that a remarkable ∼19% of all RISC-binding clusters in the miR-155 transfected NoDice(4-25) cells exhibited ≥6-nt contiguous seed homology to the miR-155 seed sequence. Similarly, ∼13% of the RISC-binding clusters detected using PAR-CLIP in the miR-K11 transfected NoDice(4-25) cells also showed ≥6-nt contiguous seed homology to the miR-K11 seed sequence, which is identical to the miR-155 seed.…”

Section: Synthetic Microrna Duplexes Efficiently Program Risc In Dicementioning

confidence: 99%

Derivation and characterization of Dicer- and microRNA-deficient human cells

Bogerd

Whisnant

Kennedy

et al. 2014

RNA

147

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We have used genome editing to generate inactivating deletion mutations in all three copies of the dicer (hdcr) gene present in the human cell line 293T. As previously shown in murine ES cells lacking Dicer function, hDcr-deficient 293T cells are severely impaired for the production of mature microRNAs (miRNAs). Nevertheless, RNA-induced silencing complexes (RISCs) present in these hDcr-deficient cells are readily programmed by transfected, synthetic miRNA duplexes to repress mRNAs bearing either fully or partially complementary targets, including targets bearing incomplete seed homology to the introduced miRNA. Using these hDcr-deficient 293T cells, we demonstrate that human pre-miRNA processing can be effectively rescued by ectopic expression of the Drosophila Dicer 1 protein, but only in the presence of the PB isoform of Loquacious (Loqs-PB), the fly homolog of the hDcr cofactor TRBP. In contrast, Drosophila Dicer 2, even in the presence of its cofactors Loqs-PD and R2D2, was unable to support human pre-miRNA processing. Interestingly, although ectopic Drosophila Dicer 1/Loqs-PB or hDcr both rescued pre-miRNA processing effectively in these hDcr-deficient cells, there were significant differences in the ratio of the miRNA isoforms that were produced, especially in the case of miR-30 family members, and we also noted differences in the relative expression level of miRNAs vs. passenger strands for a subset of human miRNAs. These data demonstrate that the mechanisms underlying the accurate processing of pre-miRNAs are largely, but not entirely, conserved between mammalian and insect cells.

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Viral MicroRNA Targetome of KSHV-Infected Primary Effusion Lymphoma Cell Lines

Cited by 272 publications

References 50 publications

Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression

Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression

RNA regulons and the RNA-protein interaction network

Derivation and characterization of Dicer- and microRNA-deficient human cells

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