DNA methylation enzymes and PRC1 restrict B-cell Epstein-Barr virus oncoprotein expression

Nat Microbiol. 2020 Aug;5(8):1051-1063. doi: 10.1038/s41564-020-0724-y. Epub 2020 May 18.


To accomplish the remarkable task of lifelong infection, the Epstein-Barr virus (EBV) switches between four viral genome latency and lytic programmes to navigate the B-cell compartment and evade immune responses. The transforming programme, consisting of highly immunogenic EBV nuclear antigen (EBNA) and latent membrane proteins (LMPs), is expressed in newly infected B lymphocytes and in post-transplant lymphomas. On memory cell differentiation and in most EBV-associated Burkitt's lymphomas, all but one viral antigen are repressed for immunoevasion. To gain insights into the epigenetic mechanisms that restrict immunogenic oncoprotein expression, a genome-scale CRISPR-Cas9 screen was performed in EBV and Burkitt's lymphoma cells. Here, we show that the ubiquitin ligase ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) and its DNA methyltransferase partner DNA methyltransferase I (DNMT1) are critical for the restriction of EBNA and LMP expression. All UHRF1 reader and writer domains were necessary for silencing and DNMT3B was identified as an upstream viral genome CpG methylation initiator. Polycomb repressive complex I exerted a further layer of control over LMP expression, suggesting a second mechanism for latency programme switching. UHRF1, DNMT1 and DNMT3B are upregulated in germinal centre B cells, the Burkitt's lymphoma cell of origin, providing a molecular link between B-cell state and the EBV latency programme. These results suggest rational therapeutic targets to manipulate EBV oncoprotein expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral
  • B-Lymphocytes / virology*
  • Burkitt Lymphoma
  • CCAAT-Enhancer-Binding Proteins
  • CRISPR-Cas Systems
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle Proteins / pharmacology*
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methylation / physiology*
  • DNA Methyltransferase 3B
  • Epstein-Barr Virus Nuclear Antigens
  • Gene Expression Regulation, Viral / drug effects*
  • Genes, Viral
  • Genome, Viral
  • Herpesvirus 4, Human / drug effects*
  • Herpesvirus 4, Human / genetics*
  • Herpesvirus 4, Human / metabolism
  • Humans
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Ubiquitin-Protein Ligases


  • Antigens, Viral
  • CCAAT-Enhancer-Binding Proteins
  • Cell Cycle Proteins
  • Epstein-Barr Virus Nuclear Antigens
  • Oncogene Proteins
  • PRC1 protein, human
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • UHRF1 protein, human
  • Ubiquitin-Protein Ligases