Regulation of HPV16 late gene expression

Acetylation of intragenic histones on HPV16 correlates with enhanced HPV16 gene expression

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Human papillomavirus type 16 (HPV16) is an oncogenic DNA virus that is relatively common in the human population. The HPV16-infections are normally cleared within a year or two, but HPV16 may in rare cases persist for longer time and give rise to lesions in the epithelium of the uterine cervix in women. This is highly unfavourable since virus particles are mot produced in these cells and the host cells may acquire mutations over time that render them malignant. The HPV16 life cycle is divided into an early and a late stage. While the early genes E6 and E7 initially drive cell proliferation to secure production of cellular DNA polymerase needed for HPV DNA replication. Eventually, expression of the late structural proteins is activated by terminal cell differentiation. The delayed production of the late immunogenic L1 and L2 proteins is highly conserved among the HPVs and is likely to allow the virus to escape the immune system of the host. We believe that failure to enter the late stage of the HPV16 life cycle, and failure to produce L1 and L2 proteins is a prerequisite for establishment of long-term persistence and development of cancer. We speculate that premature activation of the L1 and L2 production would uncover HPV16 infected cells for the immune system of the host and cause viral clearance. We are therefore interested in the regulation of HPV16 late gene expression.

HPV16 late gene expression is regulated by a switch from early-to-late promoter, early-to-late polyadenylation signal and early-to-late splice sites. We have previously identified a number of RNA-binding cellular proteins that control HPV16 RNA splicing and polyadenylation. Now we are investigating if DNA binding factors such as histones contribute to the control of HPV16 mRNA splicing and polyadenylation, perhaps by recruiting important RNA processing factors to the HPV16 genome. The short-term goal was to determine if epigenetic marks on the HPV16 genome differed between HPV16 early- and late-genes, which is what we found. In particular H3K9me3 was enriched over the late region of the HPV16 genome. The long-term goal is to determine if the histone marks on the HPV16 genome control HPV16 mRNA splicing and polyadenylation, thereby contributing to the tightly regulated switch from HPV16 early-to-late gene expression.

We were surprised to see a substantial effect of histone deacetylase inhibitors on histone acetylation over the entire HPV16 genome, in particular in HPV16-immortalised, but non-malignant cells. These histone deacetylase inhibitors activated both HPV16 early- and late-gene expression.

Schwartz

Figure 1. Speculative model of the role of histone modifications on the HPV16 genome in the regulation of HPV16 mRNA splicing. (A) The hnRNP-interacting histone H3K9me3, but not H3K9me2, is enriched over the HPV16 late region. (B) In a speculative model, H3K9me3 in the HPV16 late region interacts with hnRNPs and bring them to the newly synthesized HPV16 mRNAs. This interaction would enhance the chances that hnRNP-proteins bind HPV16 late mRNAs and suppress splicing to HPV16 late splice site SA5639.

Introducing the Authors

Schwartz Screenshot

Cecilia Johansson, Haoran Yu, Jakob Nygren, Ann-Kristin Mossberg, Tavan Jamal Fattah, Stefan Schwartz

About the research

Acetylation of intragenic histones on HPV16 correlates with enhanced HPV16 gene expression
Virology, Volume 482, August 2015, Pages 244–259
Cecilia Johansson, Tavan Jamal Fattah, Haoran Yu, Jakob Nygren, Ann-Kristin Mossberg, Stefan Schwartz

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