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Investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in Epstein–Barr virus-infected human B lymphocytes via big data mining and genome-wide two-sided NGS data identification

Epstein–Barr virus (EBV), also known as human herpesvirus 4, is prevalent in all human populations. EBV mainly infects human B lymphocytes and epithelial cells, and is therefore associated with their various malignancies. To unravel the cellular mechanisms during the infection, we constructed inters...

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Autores principales: Li, Cheng-Wei, Jheng, Bo-Ren, Chen, Bor-Sen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105016/
https://www.ncbi.nlm.nih.gov/pubmed/30133498
http://dx.doi.org/10.1371/journal.pone.0202537
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author Li, Cheng-Wei
Jheng, Bo-Ren
Chen, Bor-Sen
author_facet Li, Cheng-Wei
Jheng, Bo-Ren
Chen, Bor-Sen
author_sort Li, Cheng-Wei
collection PubMed
description Epstein–Barr virus (EBV), also known as human herpesvirus 4, is prevalent in all human populations. EBV mainly infects human B lymphocytes and epithelial cells, and is therefore associated with their various malignancies. To unravel the cellular mechanisms during the infection, we constructed interspecies networks to investigate the molecular cross-talk mechanisms between human B cells and EBV at the first (0–24 hours) and second (8–72 hours) stages of EBV infection. We first constructed a candidate genome-wide interspecies genetic-and-epigenetic network (the candidate GIGEN) by big database mining. We then pruned false positives in the candidate GIGEN to obtain the real GIGENs at the first and second infection stages in the lytic phase by their corresponding next-generation sequencing data through dynamic interaction models, the system identification approach, and the system order detection method. The real GIGENs are very complex and comprise protein–protein interaction networks, gene/microRNA (miRNA)/long non-coding RNA regulation networks, and host–virus cross-talk networks. To understand the molecular cross-talk mechanisms underlying EBV infection, we extracted the core GIGENs including host–virus core networks and host–virus core pathways from the real GIGENs using the principal network projection method. According to the results, we found that the activities of epigenetics-associated human proteins or genes were initially inhibited by viral proteins and miRNAs, and human immune responses were then dysregulated by epigenetic modification. We suggested that EBV exploits viral proteins and miRNAs, such as EBNA1, BPLF1, BALF3, BVRF1 and miR-BART14, to develop its defensive mechanism to defeat multiple immune attacks by the human immune system, promotes virion production, and facilitates the transportation of viral particles by activating the human genes NRP1 and CLIC5. Ultimately, we propose a therapeutic intervention comprising thymoquinone, valpromide, and zebularine to act as inhibitors of EBV-associated malignancies.
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spelling pubmed-61050162018-09-15 Investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in Epstein–Barr virus-infected human B lymphocytes via big data mining and genome-wide two-sided NGS data identification Li, Cheng-Wei Jheng, Bo-Ren Chen, Bor-Sen PLoS One Research Article Epstein–Barr virus (EBV), also known as human herpesvirus 4, is prevalent in all human populations. EBV mainly infects human B lymphocytes and epithelial cells, and is therefore associated with their various malignancies. To unravel the cellular mechanisms during the infection, we constructed interspecies networks to investigate the molecular cross-talk mechanisms between human B cells and EBV at the first (0–24 hours) and second (8–72 hours) stages of EBV infection. We first constructed a candidate genome-wide interspecies genetic-and-epigenetic network (the candidate GIGEN) by big database mining. We then pruned false positives in the candidate GIGEN to obtain the real GIGENs at the first and second infection stages in the lytic phase by their corresponding next-generation sequencing data through dynamic interaction models, the system identification approach, and the system order detection method. The real GIGENs are very complex and comprise protein–protein interaction networks, gene/microRNA (miRNA)/long non-coding RNA regulation networks, and host–virus cross-talk networks. To understand the molecular cross-talk mechanisms underlying EBV infection, we extracted the core GIGENs including host–virus core networks and host–virus core pathways from the real GIGENs using the principal network projection method. According to the results, we found that the activities of epigenetics-associated human proteins or genes were initially inhibited by viral proteins and miRNAs, and human immune responses were then dysregulated by epigenetic modification. We suggested that EBV exploits viral proteins and miRNAs, such as EBNA1, BPLF1, BALF3, BVRF1 and miR-BART14, to develop its defensive mechanism to defeat multiple immune attacks by the human immune system, promotes virion production, and facilitates the transportation of viral particles by activating the human genes NRP1 and CLIC5. Ultimately, we propose a therapeutic intervention comprising thymoquinone, valpromide, and zebularine to act as inhibitors of EBV-associated malignancies. Public Library of Science 2018-08-22 /pmc/articles/PMC6105016/ /pubmed/30133498 http://dx.doi.org/10.1371/journal.pone.0202537 Text en © 2018 Li et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Li, Cheng-Wei
Jheng, Bo-Ren
Chen, Bor-Sen
Investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in Epstein–Barr virus-infected human B lymphocytes via big data mining and genome-wide two-sided NGS data identification
title Investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in Epstein–Barr virus-infected human B lymphocytes via big data mining and genome-wide two-sided NGS data identification
title_full Investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in Epstein–Barr virus-infected human B lymphocytes via big data mining and genome-wide two-sided NGS data identification
title_fullStr Investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in Epstein–Barr virus-infected human B lymphocytes via big data mining and genome-wide two-sided NGS data identification
title_full_unstemmed Investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in Epstein–Barr virus-infected human B lymphocytes via big data mining and genome-wide two-sided NGS data identification
title_short Investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in Epstein–Barr virus-infected human B lymphocytes via big data mining and genome-wide two-sided NGS data identification
title_sort investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in epstein–barr virus-infected human b lymphocytes via big data mining and genome-wide two-sided ngs data identification
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105016/
https://www.ncbi.nlm.nih.gov/pubmed/30133498
http://dx.doi.org/10.1371/journal.pone.0202537
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