Epigenetic regulation of human papillomavirus transcription in the productive virus life cycle

Abstract

Human papillomaviruses (HPV) are a large family of viruses which contain a circular, double-stranded DNA genome of approximately 8000 base pairs. The viral DNA is chromatinized by the recruitment of cellular histones which are subject to host cell-mediated post-translational epigenetic modification recognized as an important mechanism of virus transcription regulation. The HPV life cycle is dependent on the terminal differentiation of the target cell within epithelia-the keratinocyte. The virus life cycle begins in the undifferentiated basal compartment of epithelia where the viral chromatin is maintained in an epigenetically repressed state, stabilized by distal chromatin interactions between the viral enhancer and early gene region. Migration of the infected keratinocyte towards the surface of the epithelium induces cellular differentiation which disrupts chromatin looping and stimulates epigenetic remodelling of the viral chromatin. These epigenetic changes result in enhanced virus transcription and activation of the virus late promoter facilitating transcription of the viral capsid proteins. In this review article, we discuss the complexity of virus-and host-cell-mediated epigenetic regulation of virus transcription with a specific focus on differentiationdependent remodelling of viral chromatin during the HPV life cycle.

Persistent Human Papillomavirus Infection

“…The coding regions of the viral genome contain between seven and nine open reading frames that are organized into early and late regions; the early region encodes the E1, E2, E1^E4, E8^E2, E5, E6, and E7 proteins and the late region encodes the L1 and L2 capsid proteins. The non-coding region, otherwise known as the upstream regulatory region (URR), is located upstream of the early region and contains multiple cis regulatory elements required for transcription, as well as the origin of replication [ 17 ]. Transcription from the viral genome occurs in three phases (early, intermediate, and late) and is intricately linked to the host epithelial differentiation program.…”

The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: a review

“…Cervical carcinogenesis is driven by the viral oncoproteins, E6 and E7. Their transcription and the HPV productive life cycle in differentiated epithelium relies on interactions with multiple cellular proteins and complex epigenetic remodelling of the viral chromatin, including both histone modifications and DNA methylation 5 . This epigenetic programme is disrupted during malignant transformation.…”

Potential biomarker of human papillomavirus 16 L1 methylation for prediction of anal intraepithelial neoplasia in men who have sex with men (MSM)

“…One study showed that HPV16 p670 late promoter was highly methylated in cervical carcinoma cases [21]. The low expression of viral early gene and lack of capsid L1/L2 proteins expression in undifferentiated basal cells could prevent activation of immune response to viral infection [22].…”