Epigenetic regulation of latent Epstein-Barr virus promoters

Abstract

Epigenotypes are modified cellular or viral genotypes that differ in transcriptional activity in spite of having an identical or nearly identical DNA sequence. Restricted expression of latent, episomal Epstein-Barr virus (EBV) genomes is a consequence of a series of epigenetic modifications. In tight latency, there is no virus production (lytic viral replication, associated with the expression of all viral genes), and only a limited set of viral promoters is activated in a host-cell-dependent manner. The latent EBV promoters control the expression of growth-transformation-associated viral genes. The role of major epigenetic mechanisms in the regulation of latent EBV promoters is variable. DNA methylation contributes to silencing of Wp and Cp (alternative promoters for transcripts coding for nuclear antigens EBNA 1-6) and LMP1p, LMP2Ap and LMP2Bp (promoters for transcripts encoding transmembrane proteins). DNA methylation does not control, however, Qp (a promoter for EBNA1 transcripts only) in B lymphoblastoid cell lines (LCLs, immortalized by EBV in vitro), although in vitro methylated Qp-reporter gene constructs are silenced. The invariably unmethylated Qp is probably switched off by binding of a repressor protein in LCLs. Histone modifications may also contribute to the regulation of latent EBV promoters because the active Cp, Qp and LMP2Ap promoters that are marked by strong binding of cellular regulatory proteins are located on "acetylation islands" enriched in diacetylated histone H3 and tetraacetylated histone H4. We speculate that binding of the chromatin insulator protein CTCF to 3 distinct sites (within, close to and far from the matrix attachment region) may contribute to the three-dimensional organization of the viral episomes. We also raise the point that latent EBV episomes may relocate to new nuclear subcompartments before the start of lytic EBV replication. We propose that a similar relocation of EBV episomes may result in a promoter switch (from Qp to Cp) due to the access of Cp to a B-lymphoblast-specific transcription factory when in vitro cultivated Burkitt's lymphoma cells undergo a phenotypic drift.