4.7 Article

A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism

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PLOS PATHOGENS
卷 17, 期 1, 页码 -

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PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1009208

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资金

  1. Cancer Center Core Grant [P30 CA010815]
  2. NIH [RO1 CA093606, R01 DE017336, R50 CA221838]
  3. Novo Nordisk Foundation Center for Stem Cell Biology through Novo Nordisk Foundation [NNF17CC0027852]

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EBV immortalizes resting B-lymphocytes through orchestrated reprogramming of chromatin structure, transcription, and metabolism. The virus alters accessible chromatin, leading to complex transcriptional responses and changes in nucleotide metabolism. Purine metabolism, particularly the role of adenosine deaminase, emerges as a major therapeutic target in EBV-driven lymphoid cancers. This study highlights the importance of purine metabolism and ADA in EBV-induced immortalization process.
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. Author summary EBV immortalization recapitulates aspects of natural B-cell development from germinal center reaction to memory B-cell differentiation. Here, we provide an integrated multi-omic approach to investigating the EBV-induced changes in B-cell transcriptome using RNA-seq, epigenome by ATAC-seq, and metabolome by mass spectrometry of polar metabolites. We identify purine metabolism as a major pathway that is significantly altered by EBV in each data set. We focus on EBNA1 and find that it binds directly to enhancer elements in a subset of genes, including key regulators of purine metabolism such as adenosine deaminase (ADA) and adenylate kinase 4 (AK4). EBV immortalized B-cells are strongly dependent on ADA for proliferation and inhibitors of ADA prevent B-cell immortalization by EBV. These findings identify purine metabolism as a major pathway targeted by EBV during primary infection and suggest that EBNA1 functions as a pioneering transcription factor that reprograms key regulatory genes in purine metabolism pathway.

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