Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalities
Abstract Background Epstein–Barr virus (EBV) targets B-cells where it establishes a latent infection. EBV can transform B-cells in vitro and is recognized as an oncogenic virus, especially in the setting of immune compromise. Indeed, immunodeficient patients may fail to control chronic EBV infection...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-06-01
|
| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-021-01904-3 |
| _version_ | 1818741099199463424 |
|---|---|
| author | Moussab Tatfi Emeline Perthame Kenzo-Hugo Hillion Marie-Agnès Dillies Hervé Menager Olivier Hermine Felipe Suarez |
| author_facet | Moussab Tatfi Emeline Perthame Kenzo-Hugo Hillion Marie-Agnès Dillies Hervé Menager Olivier Hermine Felipe Suarez |
| author_sort | Moussab Tatfi |
| collection | DOAJ |
| description | Abstract Background Epstein–Barr virus (EBV) targets B-cells where it establishes a latent infection. EBV can transform B-cells in vitro and is recognized as an oncogenic virus, especially in the setting of immune compromise. Indeed, immunodeficient patients may fail to control chronic EBV infection, leading to the development EBV-driven lymphoid malignancies. Ataxia telangiectasia (AT) is a primary immune deficiency caused by mutations in the ATM gene, involved in the repair of double-strand breaks. Patients with AT are at high risk of developing cancers, mostly B-cell lymphoid malignancies, most of which being EBV-related. Aside from immune deficiency secondary to AT, loss of ATM function could also hinder the control of the virus within B-cells, favoring lymphomagenesis in AT patients. Results We used RNA sequencing on lymphoblastoid cell lines derived from patients with AT and healthy donors to analyze and compare both cellular and viral gene expression. We found numerous deregulated signaling pathways involving transcription, translation, oncogenesis and immune regulation. Specifically, the translational defect was confirmed in vitro, suggesting that the pathogenesis of AT may also involve a ribosomal defect. Concomitant analysis of viral gene expression did not reveal significant differential gene expression, however, analysis of EBV interactome suggests that the viral latency genes EBNA-3A, EBNA-3C and LMP1 may be disrupted in LCL from AT patients. Conclusion Our data support the notion that ATM deficiency deregulates cellular gene expression possibly disrupting interactions with EBV latent genes, promoting the oncogenic potential of the virus. These preliminary findings provide a new step towards the understanding of EBV regulation and of AT pathogenesis. |
| first_indexed | 2024-12-18T01:51:14Z |
| format | Article |
| id | doaj.art-5332e9a34cab45e5a6a33e59c6d46ca0 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-18T01:51:14Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-5332e9a34cab45e5a6a33e59c6d46ca02022-12-21T21:25:02ZengBMCOrphanet Journal of Rare Diseases1750-11722021-06-0116111110.1186/s13023-021-01904-3Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalitiesMoussab Tatfi0Emeline Perthame1Kenzo-Hugo Hillion2Marie-Agnès Dillies3Hervé Menager4Olivier Hermine5Felipe Suarez6INSERM U1163/CNRS ERL8254 - Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Institut ImagineHub de Bioinformatique et Biostatistique – Département Biologie Computationnelle, Institut PasteurHub de Bioinformatique et Biostatistique – Département Biologie Computationnelle, Institut PasteurHub de Bioinformatique et Biostatistique – Département Biologie Computationnelle, Institut PasteurHub de Bioinformatique et Biostatistique – Département Biologie Computationnelle, Institut PasteurINSERM U1163/CNRS ERL8254 - Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Institut ImagineINSERM U1163/CNRS ERL8254 - Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Institut ImagineAbstract Background Epstein–Barr virus (EBV) targets B-cells where it establishes a latent infection. EBV can transform B-cells in vitro and is recognized as an oncogenic virus, especially in the setting of immune compromise. Indeed, immunodeficient patients may fail to control chronic EBV infection, leading to the development EBV-driven lymphoid malignancies. Ataxia telangiectasia (AT) is a primary immune deficiency caused by mutations in the ATM gene, involved in the repair of double-strand breaks. Patients with AT are at high risk of developing cancers, mostly B-cell lymphoid malignancies, most of which being EBV-related. Aside from immune deficiency secondary to AT, loss of ATM function could also hinder the control of the virus within B-cells, favoring lymphomagenesis in AT patients. Results We used RNA sequencing on lymphoblastoid cell lines derived from patients with AT and healthy donors to analyze and compare both cellular and viral gene expression. We found numerous deregulated signaling pathways involving transcription, translation, oncogenesis and immune regulation. Specifically, the translational defect was confirmed in vitro, suggesting that the pathogenesis of AT may also involve a ribosomal defect. Concomitant analysis of viral gene expression did not reveal significant differential gene expression, however, analysis of EBV interactome suggests that the viral latency genes EBNA-3A, EBNA-3C and LMP1 may be disrupted in LCL from AT patients. Conclusion Our data support the notion that ATM deficiency deregulates cellular gene expression possibly disrupting interactions with EBV latent genes, promoting the oncogenic potential of the virus. These preliminary findings provide a new step towards the understanding of EBV regulation and of AT pathogenesis.https://doi.org/10.1186/s13023-021-01904-3EBVATMAtaxiaRNA-seqLymphoma |
| spellingShingle | Moussab Tatfi Emeline Perthame Kenzo-Hugo Hillion Marie-Agnès Dillies Hervé Menager Olivier Hermine Felipe Suarez Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalities Orphanet Journal of Rare Diseases EBV ATM Ataxia RNA-seq Lymphoma |
| title | Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalities |
| title_full | Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalities |
| title_fullStr | Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalities |
| title_full_unstemmed | Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalities |
| title_short | Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalities |
| title_sort | gene expression analysis in ebv infected ataxia telangiectasia cell lines by rna sequencing reveals protein synthesis defect and immune abnormalities |
| topic | EBV ATM Ataxia RNA-seq Lymphoma |
| url | https://doi.org/10.1186/s13023-021-01904-3 |
| work_keys_str_mv | AT moussabtatfi geneexpressionanalysisinebvinfectedataxiatelangiectasiacelllinesbyrnasequencingrevealsproteinsynthesisdefectandimmuneabnormalities AT emelineperthame geneexpressionanalysisinebvinfectedataxiatelangiectasiacelllinesbyrnasequencingrevealsproteinsynthesisdefectandimmuneabnormalities AT kenzohugohillion geneexpressionanalysisinebvinfectedataxiatelangiectasiacelllinesbyrnasequencingrevealsproteinsynthesisdefectandimmuneabnormalities AT marieagnesdillies geneexpressionanalysisinebvinfectedataxiatelangiectasiacelllinesbyrnasequencingrevealsproteinsynthesisdefectandimmuneabnormalities AT hervemenager geneexpressionanalysisinebvinfectedataxiatelangiectasiacelllinesbyrnasequencingrevealsproteinsynthesisdefectandimmuneabnormalities AT olivierhermine geneexpressionanalysisinebvinfectedataxiatelangiectasiacelllinesbyrnasequencingrevealsproteinsynthesisdefectandimmuneabnormalities AT felipesuarez geneexpressionanalysisinebvinfectedataxiatelangiectasiacelllinesbyrnasequencingrevealsproteinsynthesisdefectandimmuneabnormalities |