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BJAB Cell Lines Unmodified, Transduced with ith lentiviral vector pNL-SIN-CMV-AcGFP or pNL-SIN-CMV-AcGFP/miR-K12-11

ABSTRACT: All metazoan eukaryotes express microRNAs (miRNAs), ~22 nt long regulatory RNAs that can repress the expression of mRNAs bearing complementary sequences. Several DNA viruses also express miRNAs in infected cells, suggesting a role in viral replication and pathogenesis. While specific viral miRNAs have been shown to autoregulate viral mRNAs or downregulate cellular mRNAs via novel target sites, the function of the majority of viral miRNAs remains unknown. Here, we report that the miR-K12-11 miRNA encoded by Kaposi’s Sarcoma Associated Herpesvirus (KSHV) shows significant homology to cellular miR-155, including the entire miRNA “seed” region. Using a range of assays, we demonstrate that expression of physiological levels of miRK12- 11 or miR-155 results in the downregulation of an extensive set of common mRNA targets, including genes with known roles in cell growth regulation. Our findings indicate that viral miR-K12-11 functions as an ortholog of cellular miR-155 and has likely evolved to exploit a pre-existing gene regulatory pathway in B-cells. Moreover, the known etiological role of miR-155 in B-cell transformation suggests the possibility that miR-K12-11 may contribute to the induction of KSHV positive B-cell tumors in infected patients. Keywords: miRNA stable expression comparisons

ORGANISM(S): Homo sapiens

PROVIDER: GSE8867 | GEO | 2007/12/19

SECONDARY ACCESSION(S): PRJNA102233

REPOSITORIES: GEO

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Project description:Background: Kaposi’s sarcoma associated herpes virus (KSHV) is associated with tumors of endothelial and lymphoid origin. During latent infection, KSHV expresses miR-K12-11, an ortholog of the human tumor gene hsa-miR-155. Both gene products are microRNAs (miRNAs), which are important post-transcriptional regulators that contribute to tissue specific gene expression. Advances in target identification technologies and molecular interaction databases have allowed a systems biology approach to unravel the gene regulatory networks (GRNs) triggered by miR-K12-11 in endothelial and lymphoid cells. Understanding the tissue specific function of miR-K12-11 will help to elucidate underlying mechanisms of KSHV pathogenesis. Results: Ectopic expression of miR-K12-11 differentially affected gene expression in BJAB cells of lymphoid origin and TIVE cells of endothelial origin. Direct miRNA targeting accounted for a small fraction of the observed transcriptome changes: only 29 common genes were identified as putative direct targets of miR-K12-11 in both cell types. However, a number of commonly affected biological pathways, such as carbohydrate metabolism and interferon response related signaling, were revealed by gene ontology analysis. Integration of transcriptome profiling, bioinformatic algorithms, and databases of protein-protein interactome from the ENCODE project identified different nodes of GRNs utilized by miR-K12-11 in a tissue-specific fashion. These effector genes, including cancer associated transcription factors (TFs) and signaling proteins, amplified the regulatory potential of a single miRNA, from a small set of putative direct targets to a larger set of genes. Conclusions: This is the first comparative analysis of miRNA-K12-11’s effects in endothelial and B cells, from tissues infected with KSHV in vivo. MiR-K12-11 was able to broadly modulate gene expression in both cell types. Using a systems biology approach, we inferred that miR-K12-11 establishes its GRN by both repressing master TFs and influencing signaling pathways, to counter the host anti-viral response and to promote proliferation and survival of infected cells. The targeted GRNs are more reproducible and informative than target gene identification, and our approach can be applied to other regulatory factors of interest.

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BJAB Cell Lines Unmodified, Transduced with ith lentiviral vector pNL-SIN-CMV-AcGFP or pNL-SIN-CMV-AcGFP/miR-K12-11

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