Viral epigenetics

Abstract

DNA tumor viruses including members of the polyomavirus, adenovirus, papillomavirus, and herpes virus families are presently the subject of intense interest with respect to the role that epigenetics plays in control of the virus life cycle and the transformation of a normal cell to a cancer cell. To date, these studies have primarily focused on the role of histone modification, nucleosome location, and DNA methylation in regulating the biological consequences of infection. Using a wide variety of strategies and techniques ranging from simple ChIP to ChIP-chip and ChIP-seq to identify histone modifications, nuclease digestion to genome wide next generation sequencing to identify nucleosome location, and bisulfite treatment to MeDIP to identify DNA methylation sites, the epigenetic regulation of these viruses is slowly becoming better understood. While the viruses may differ in significant ways from each other and cellular chromatin, the role of epigenetics appears to be relatively similar. Within the viral genome nucleosomes are organized for the expression of appropriate genes with relevant histone modifications particularly histone acetylation. DNA methylation occurs as part of the typical gene silencing during latent infection by herpesviruses. In the simple tumor viruses like the polyomaviruses, adenoviruses, and papillomaviruses, transformation of the cell occurs via integration of the virus genome such that the virus's normal regulation is disrupted. This results in the unregulated expression of critical viral genes capable of redirecting cellular gene expression. The redirected cellular expression is a consequence of either indirect epigenetic regulation where cellular signaling or transcriptional dysregulation occurs or direct epigenetic regulation where epigenetic cofactors such as histone deacetylases are targeted. In the more complex herpersviruses transformation is a consequence of the expression of the viral latency proteins and RNAs which again can have either a direct or indirect effect on epigenetic regulation of cellular expression. Nevertheless, many questions still remain with respect to the specific mechanisms underlying epigenetic regulation of the viruses and transformation.

Figures

Fig. 1. Major forms of epigenetic regulation

Fig. 2

Schematic representation of the polyomavirus genome. The organization of a typical polyomavirus (SV40) is shown. The early proteins T-antigen and t-antigen, the late proteins VP1-4 and the agnogene protein, and the origin of replication (ori) within the regulatory region are indicated

Fig. 3

Schematic representation of the papillomavirus genome. The organization of a typical oncogenic human papillomavirus (HPV16) is shown. The early proteins E1–7, the late proteins L1 and L2, and the origin of replication (ori) within the upstream regulatory region (URR) are indicated

Fig. 4

Schematic representation of the adenovirus genome. The organization of a typical adenovirus (adenovirus 5) genome including the early proteins E1–4, the late proteins L1–5, and the terminal repeats (ITR) are indicated

Fig. 5

Schematic representation of the herpesvirus genome. The organization of the episomal form of a typical oncogenic human herpesvirus (EBV) is shown. The location of the latency proteins EBNA1–3, EBNA-LP, LMP1, and LMP2 are indicated. The lytic origin of replication is also indicated (ori)