EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency
| Autor: | Christine T. Styles, Kostas Paschos, Gillian A. Parker, Martin J. Allday, Quentin Bazot, Robert E. White |
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| Přispěvatelé: | Medical Research Council (MRC), Wellcome Trust |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Life Sciences & Biomedicine - Other Topics Epstein-Barr Virus Infections Herpesvirus 4 Human B Cells LYTIC REACTIVATION Cellular differentiation Gene Expression Plasma cell medicine.disease_cause Biochemistry White Blood Cells 0302 clinical medicine Animal Cells hemic and lymphatic diseases GERMINAL CENTER Plasma cell differentiation Virus latency Medicine and Health Sciences TUMOR-SUPPRESSOR TRANSCRIPTION Biology (General) EPSTEIN-BARR-VIRUS Pathology and laboratory medicine 11 Medical and Health Sciences B-Lymphocytes Chromosome Biology General Neuroscience Cell Differentiation NUCLEAR-PROTEIN EBNA3C HUMANIZED MICE Medical microbiology Chromatin Recombinant Proteins 3. Good health Virus Latency Histone Code medicine.anatomical_structure 030220 oncology & carcinogenesis Viruses Epigenetics Cellular Types Pathogens General Agricultural and Biological Sciences Life Sciences & Biomedicine Research Article Herpesviruses Biochemistry & Molecular Biology QH301-705.5 Immune Cells Immunology DNA transcription Plasma Cells Immunoglobulins CDK INHIBITOR P18(INK4C) Biology Microbiology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Viral Proteins Cell Line Tumor 07 Agricultural and Veterinary Sciences DNA-binding proteins medicine Genetics Epstein-Barr virus Cyclin-Dependent Kinase Inhibitor p18 Humans Gene Regulation Antibody-Producing Cells B cell Blood Cells Science & Technology General Immunology and Microbiology Organisms Viral pathogens Biology and Life Sciences Proteins Cell Biology 06 Biological Sciences medicine.disease Epstein–Barr virus Molecular biology Microbial pathogens Regulatory Proteins Repressor Proteins 030104 developmental biology ESTROGEN-RECEPTOR Positive Regulatory Domain I-Binding Factor 1 DNA viruses Chromatin immunoprecipitation Biomarkers Transcription Factors GENERATION Developmental Biology |
| Zdroj: | PLoS Biology PLoS Biology, Vol 15, Iss 8, p e2001992 (2017) |
| Popis: | Mature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, and proliferate. If the cells are infected ex vivo, they are transformed into continuously proliferating lymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes, express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activated B-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), in which EBV persistence is established. Three related latency-associated viral proteins EBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellular genes. EBNA3B is not necessary to establish LCLs, but EBNA3A and EBNA3C are required to sustain proliferation, in part, by repressing the expression of tumour suppressor genes. Here we show, using EBV-recombinants in which both EBNA3A and EBNA3C can be conditionally inactivated or using virus completely lacking the EBNA3 gene locus, that—after a phase of rapid proliferation—infected primary B cells express elevated levels of factors associated with plasma cell (PC) differentiation. These include the cyclin-dependent kinase inhibitor (CDKI) p18INK4c, the master transcriptional regulator of PC differentiation B lymphocyte-induced maturation protein-1 (BLIMP-1), and the cell surface antigens CD38 and CD138/Syndecan-1. Chromatin immunoprecipitation sequencing (ChIP-seq) and chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) indicate that in LCLs inhibition of CDKN2C (p18INK4c) and PRDM1 (BLIMP-1) transcription results from direct binding of EBNA3A and EBNA3C to regulatory elements at these loci, producing stable reprogramming. Consistent with the binding of EBNA3A and/or EBNA3C leading to irreversible epigenetic changes, cells become committed to a B-blast fate Author summary Epstein-Barr virus (EBV) infection can cause several types of cancer associated with its major target in humans, the mature B cell. Furthermore, EBV is one of the most potent transforming agents ever identified, producing—in vitro—‘immortal’ B lymphoblastoid cell lines (LCLs) with outstanding reliability. However, the near-symbiotic relationship between EBV and its natural host (>95% of human adults are asymptomatically infected) provides a powerful argument that this gamma-herpesvirus did not primarily evolve to be a harmful tumour-causing virus. Consistent with this, we show here that 2 of the potentially oncogenic viral proteins (EBNA3A and EBNA3C) have evolved not to facilitate oncogenic progression but to block plasma cell differentiation in EBV-activated B cells. Specifically, they act to interrupt the gene regulation network that drives activated B cells to become terminally differentiated, quiescent plasma cells, thus allowing for sustained regeneration of virally infected B cells. EBNA3A and EBNA3C achieve this by epigenetically inhibiting expression of cellular genes essential for the differentiation pathway; these include the cyclin-dependent kinase inhibitor p18INK4c and the transcription factor BLIMP-1. This favours the establishment of EBV latency in long-lived memory B cells and therefore helps maintain a ubiquitous, generally asymptomatic infection in human populations. |
| Databáze: | OpenAIRE |
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