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Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes

Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroa...

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Autores principales: Soldan, Samantha S., Su, Chenhe, Lamontagne, R. Jason, Grams, Nicholas, Lu, Fang, Zhang, Yue, Gesualdi, James D., Frase, Drew M., Tolvinski, Lois E., Martin, Kayla, Messick, Troy E., Fingerut, Jonathan T., Koltsova, Ekaterina, Kossenkov, Andrew, Lieberman, Paul M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216538/
https://www.ncbi.nlm.nih.gov/pubmed/34106998
http://dx.doi.org/10.1371/journal.ppat.1009618
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author Soldan, Samantha S.
Su, Chenhe
Lamontagne, R. Jason
Grams, Nicholas
Lu, Fang
Zhang, Yue
Gesualdi, James D.
Frase, Drew M.
Tolvinski, Lois E.
Martin, Kayla
Messick, Troy E.
Fingerut, Jonathan T.
Koltsova, Ekaterina
Kossenkov, Andrew
Lieberman, Paul M.
author_facet Soldan, Samantha S.
Su, Chenhe
Lamontagne, R. Jason
Grams, Nicholas
Lu, Fang
Zhang, Yue
Gesualdi, James D.
Frase, Drew M.
Tolvinski, Lois E.
Martin, Kayla
Messick, Troy E.
Fingerut, Jonathan T.
Koltsova, Ekaterina
Kossenkov, Andrew
Lieberman, Paul M.
author_sort Soldan, Samantha S.
collection PubMed
description Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS).
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spelling pubmed-82165382021-07-01 Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes Soldan, Samantha S. Su, Chenhe Lamontagne, R. Jason Grams, Nicholas Lu, Fang Zhang, Yue Gesualdi, James D. Frase, Drew M. Tolvinski, Lois E. Martin, Kayla Messick, Troy E. Fingerut, Jonathan T. Koltsova, Ekaterina Kossenkov, Andrew Lieberman, Paul M. PLoS Pathog Research Article Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS). Public Library of Science 2021-06-09 /pmc/articles/PMC8216538/ /pubmed/34106998 http://dx.doi.org/10.1371/journal.ppat.1009618 Text en © 2021 Soldan et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://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
Soldan, Samantha S.
Su, Chenhe
Lamontagne, R. Jason
Grams, Nicholas
Lu, Fang
Zhang, Yue
Gesualdi, James D.
Frase, Drew M.
Tolvinski, Lois E.
Martin, Kayla
Messick, Troy E.
Fingerut, Jonathan T.
Koltsova, Ekaterina
Kossenkov, Andrew
Lieberman, Paul M.
Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes
title Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes
title_full Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes
title_fullStr Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes
title_full_unstemmed Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes
title_short Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes
title_sort epigenetic plasticity enables cns-trafficking of ebv-infected b lymphocytes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216538/
https://www.ncbi.nlm.nih.gov/pubmed/34106998
http://dx.doi.org/10.1371/journal.ppat.1009618
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