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A systems biology approach identified different regulatory networks targeted by KSHV miR-K12-11 in B cells and endothelial cells.

ABSTRACT: 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.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 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 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.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.

SUBMITTER: Yang Y

PROVIDER: S-EPMC4147158 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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A systems biology approach identified different regulatory networks targeted by KSHV miR-K12-11 in B cells and endothelial cells.

Yang Yajie Y Boss Isaac W IW McIntyre Lauren M LM Renne Rolf R

BMC genomics 20140808

<h4>Background</h4>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 ...[more]

PMID: 25106478

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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.

Project description:MotivationThe growing complexity of reaction-based models necessitates early detection and resolution of model errors. Considerable work has been done on the detection of mass balance errors, especially atomic mass analysis (AMA) (which compares the counts of atoms in the reactants and products) and Linear Programming analysis (which detects stoichiometric inconsistencies). This article extends model error checking to include: (i) certain structural errors in reaction networks and (ii) error isolation. First, we consider the balance of chemical structures (moieties) between reactants and products. This balance is expected in many biochemical reactions, but the imbalance of chemical structures cannot be detected if the analysis is done in units of atomic masses. Second, we improve on error isolation for stoichiometric inconsistencies by identifying a small number of reactions and/or species that cause the error. Doing so simplifies error remediation.ResultsWe propose two algorithms that address isolating structural errors in reaction networks. Moiety analysis finds imbalances of moieties using the same algorithm as AMA, but moiety analysis works in units of moieties instead of atomic masses. We argue for the value of checking moiety balance, and discuss two approaches to decomposing chemical species into moieties. Graphical Analysis of Mass Equivalence Sets (GAMES) provides isolation for stoichiometric inconsistencies by constructing explanations that relate errors in the structure of the reaction network to elements of the reaction network. We study the effectiveness of moiety analysis and GAMES on curated models in the BioModels repository. We have created open source codes for moiety analysis and GAMES.Availability and implementationOur project is hosted at https://github.com/ModelEngineering/SBMLLint, which contains examples, documentation, source code files and build scripts used to create SBMLLint. Our source code is licensed under the MIT open source license.Supplementary informationSupplementary data are available at Bioinformatics online.

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A systems biology approach identified different regulatory networks targeted by KSHV miR-K12-11 in B cells and endothelial cells.

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A systems biology approach identified different regulatory networks targeted by KSHV miR-K12-11 in B cells and endothelial cells.

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