The unmethylated state of the promoter/leader and 5′-regions of integrated adenovirus genes correlates with gene expression.

Abstract

An inverse correlation has been established between the levels of DNA methylation at 5′‐CCGG‐3′ (MspI/HpaII) sites in specific genes of integrated viral DNA in adenovirus type 12 (Ad12)‐transformed hamster cell lines and the extent to which these genes are expressed (Sutter and Doerfler, 1979, 1980). In general, early genes are transcribed into mRNA, while late genes are permanently switched off in these cell lines. Adenovirus type 2 genes methylated in vitro at 5′‐CCGG‐3′ sites are not transcribed upon microinjection into nuclei of Xenopus laevis oocytes ‐ unmethylated genes are expressed (Vardimon et al., 1982a). The MspI sites in the early and in some of the late Ad12 genes in cell lines HA12 /7, T637, and A2497 ‐3 have now been precisely mapped. The data presented here reveal that the promoter/leader and 5′‐regions of the early genes are unmethylated both at MspI sites and at 5′‐GCGC‐3′ (HhaI) sites. In some instances, e.g., in the E2a regions in all three lines, the main parts of the early genes are partly methylated, even though the genes are expressed. In cell line HA12 /7, the early region E3 is not expressed, and the promoter/leader and 5′‐regions of this segment are fully methylated. All late regions are completely methylated. The results suggest that the state of methylation in the promoter/leader and 5′‐regions of integrated adenovirus genes is important in the control of gene expression.

Primary DNA sequence determines sites of maintenance and de novo methylation by mammalian DNA methyltransferases.

“…Evidence that the level of methylation of specific CpG sites located near the 5' end of certain genes can block active expression of these genes has been demonstrated in a few diverse systems (4,8,9,17). In these studies, the state of methylation of specific CpG sites within the globin, adenine specific DNA methyltransferase that recognizes the pattern phosphoribosyltransferase, and adenovirus genes correlated of methyl-C on the parent strand as the determinant for with expression of these genes, demonstrating the impormaintenance methylation (6,14).…”

Host-Cell-Determined Methylation of Specific Epstein-Barr Virus Promoters Regulates the Choice between Distinct Viral Latency Programs

“…CpG methylation is believed to silence transcription from integrated retroviral genomes until later cellular events (e.g., cellular differentiation) trigger demethylation and reactivation of the retroviral genome (3,19,25,26). Additionally, analyses of gene expression from integrated adenovirus genomes have demonstrated a strong correlation between CpG methylation of specific adenovirus promoters and silenced transcription from the corresponding viral genes (37,39). Several other examples of repression of viral gene expression by host-cell-determined methylation of viral DNA sequences have been reported; these include Marek's disease virus (20,31), simian foamy virus type 3 (72), and Epstein-Barr virus (EBV) (see below).…”

DNA Methylation and Differentiation

“…In addition, methyltransferase enzymes probably mediate de novo methylation by imposing sequence-specific DNA methylation at sites previously not methylated (36,37). De (38), mouse embryo fibroblast variants (39), viral systems (40,41), and during the establishment of immortal murine cell lines (42). Such alterations in methylation patterns may represent regulatory signals which, directly or indirectly, elicit changes in gene expression.…”