A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism.
Epstein-Barr virus (EBV) immortalizes resting B-lymphocytes through a highly orchestrated reprogramming of host chromatin structure, transcription and metabolism. Here, we use a multi-omics-based approach to investigate these underlying mechanisms. ATAC-seq analysis of cellular chromatin showed that...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-01-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009208&type=printable |
| _version_ | 1826554739970539520 |
|---|---|
| author | R Jason Lamontagne Samantha S Soldan Chenhe Su Andreas Wiedmer Kyoung Jae Won Fang Lu Aaron R Goldman Jayamanna Wickramasinghe Hsin-Yao Tang David W Speicher Louise Showe Andrew V Kossenkov Paul M Lieberman |
| author_facet | R Jason Lamontagne Samantha S Soldan Chenhe Su Andreas Wiedmer Kyoung Jae Won Fang Lu Aaron R Goldman Jayamanna Wickramasinghe Hsin-Yao Tang David W Speicher Louise Showe Andrew V Kossenkov Paul M Lieberman |
| author_sort | R Jason Lamontagne |
| collection | DOAJ |
| description | Epstein-Barr virus (EBV) immortalizes resting B-lymphocytes through a highly orchestrated reprogramming of host chromatin structure, transcription and metabolism. Here, we use a multi-omics-based approach to investigate these underlying mechanisms. ATAC-seq analysis of cellular chromatin showed that EBV alters over a third of accessible chromatin during the infection time course, with many of these sites overlapping transcription factors such as PU.1, Interferon Regulatory Factors (IRFs), and CTCF. Integration of RNA-seq analysis identified a complex transcriptional response and associations with EBV nuclear antigens (EBNAs). Focusing on EBNA1 revealed enhancer-binding activity at gene targets involved in nucleotide metabolism, supported by metabolomic analysis which indicated that adenosine and purine metabolism are significantly altered by EBV immortalization. We further validated that adenosine deaminase (ADA) is a direct and critical target of the EBV-directed immortalization process. These findings reveal that purine metabolism and ADA may be useful therapeutic targets for EBV-driven lymphoid cancers. |
| first_indexed | 2024-12-13T00:56:55Z |
| format | Article |
| id | doaj.art-48776a669bd044a5a1887f85a9a8d95d |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2025-03-14T07:45:43Z |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-48776a669bd044a5a1887f85a9a8d95d2025-03-03T05:32:11ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-01-01171e100920810.1371/journal.ppat.1009208A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism.R Jason LamontagneSamantha S SoldanChenhe SuAndreas WiedmerKyoung Jae WonFang LuAaron R GoldmanJayamanna WickramasingheHsin-Yao TangDavid W SpeicherLouise ShoweAndrew V KossenkovPaul M LiebermanEpstein-Barr virus (EBV) immortalizes resting B-lymphocytes through a highly orchestrated reprogramming of host chromatin structure, transcription and metabolism. Here, we use a multi-omics-based approach to investigate these underlying mechanisms. ATAC-seq analysis of cellular chromatin showed that EBV alters over a third of accessible chromatin during the infection time course, with many of these sites overlapping transcription factors such as PU.1, Interferon Regulatory Factors (IRFs), and CTCF. Integration of RNA-seq analysis identified a complex transcriptional response and associations with EBV nuclear antigens (EBNAs). Focusing on EBNA1 revealed enhancer-binding activity at gene targets involved in nucleotide metabolism, supported by metabolomic analysis which indicated that adenosine and purine metabolism are significantly altered by EBV immortalization. We further validated that adenosine deaminase (ADA) is a direct and critical target of the EBV-directed immortalization process. These findings reveal that purine metabolism and ADA may be useful therapeutic targets for EBV-driven lymphoid cancers.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009208&type=printable |
| spellingShingle | R Jason Lamontagne Samantha S Soldan Chenhe Su Andreas Wiedmer Kyoung Jae Won Fang Lu Aaron R Goldman Jayamanna Wickramasinghe Hsin-Yao Tang David W Speicher Louise Showe Andrew V Kossenkov Paul M Lieberman A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism. PLoS Pathogens |
| title | A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism. |
| title_full | A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism. |
| title_fullStr | A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism. |
| title_full_unstemmed | A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism. |
| title_short | A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism. |
| title_sort | multi omics approach to epstein barr virus immortalization of b cells reveals ebna1 chromatin pioneering activities targeting nucleotide metabolism |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009208&type=printable |
| work_keys_str_mv | AT rjasonlamontagne amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT samanthassoldan amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT chenhesu amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT andreaswiedmer amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT kyoungjaewon amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT fanglu amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT aaronrgoldman amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT jayamannawickramasinghe amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT hsinyaotang amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT davidwspeicher amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT louiseshowe amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT andrewvkossenkov amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT paulmlieberman amultiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT rjasonlamontagne multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT samanthassoldan multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT chenhesu multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT andreaswiedmer multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT kyoungjaewon multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT fanglu multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT aaronrgoldman multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT jayamannawickramasinghe multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT hsinyaotang multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT davidwspeicher multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT louiseshowe multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT andrewvkossenkov multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism AT paulmlieberman multiomicsapproachtoepsteinbarrvirusimmortalizationofbcellsrevealsebna1chromatinpioneeringactivitiestargetingnucleotidemetabolism |