PhD Studentship: Exploration of the global manipulation of transcriptional networks by oncogenic hu

Background

Human papillomaviruses (HPV) cause 610,000 cancers per year of the anogenital and oropharyngeal tracts. HPV life cycle completion is dependent on the differentiation of infected keratinocytes. Infection is established in the undifferentiated basal keratinocytes where the chromatinised viral DNA is established as a persistent episome and viral transcripts that encode the E6 and E7 oncoproteins are expressed. Differentiation and migration of cells to the upper epithelium coincides with activation of the late virus promoter and expression of late capsid proteins. This differentiation-dependent model of the HPV life cycle is well accepted but the molecular mechanisms controlling viral gene expression remain largely unknown. HPV utilises a plethora of host transcription factors to co-ordinate these complex transcriptional events. Recently, we demonstrated that the host chromatin regulator CTCF (CCCTC-binding factor) is recruited to oncogenic HPV genomes to co-ordinate differentiation-dependent repression of viral oncogenes.

As well as controlling expression of their own genes, viruses create a host environment that supports replication. Whilst there is evidence that individual HPV proteins can alter cellular gene expression to evade immune activation and increase cellular growth, the mechanisms of virus mediated transcriptional reprogramming during the virus life cycle are not understood.

Hypothesis

HPV epigenetically reprograms the host to create a cellular milieu supportive of viral persistence and these changes contribute to HPV-driven carcinogenesis.

Aim

The student will use state-of-the-art models of HPV infected tissue and advanced technological methods to explore the complexity of genome-wide manipulation of the host and resulting transcriptional changes that contribute to HPV driven cancer.

This aim will be met by the exploration of three key objectives:

1. Analyse host transcription changes following HPV establishment in primary keratinocytes
2. Analyse the mechanistic underpinnings of HPV-mediated host transcriptional reprogramming
3. Analyse the global remodelling of host cell chromatin structure and topologically associating domains (TADs) by HPV

Completion of these aims will provide a unique overview of host manipulation by oncogenic HPV to gain novel insight into how the virus transforms cells and facilitates cancer development.
Further discussion of the project scope and aims with the supervisors is strongly encouraged.

Person Specification

Applicants should have a strong background in molecular and cellular biology, and ideally a background in the study of transcription control and/or epigenetic transcription regulation. Experience with bioinformatic analysis of RNA-Seq or ChIP-Seq data is favourable. They should have a commitment to research in viral oncology and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in biological sciences.

Funding Notes

Due to the nature of funding attached to this studentship we are not able to accept applications from overseas applicants

References

1. Paris, C., Pentland, I., Groves, I., Roberts, D.C., Coleman, N., Roberts, S. and Parish J.L. CCCTC-Binding Factor Recruitment to the Early Region of the Human Papillomavirus Type 18 Genome Regulates Viral Oncogene Expression. (2015) Journal of Virology. 89(9):4770-85.
2. Siddiqa, A., Campos-Leon K., James, C., Roberts, S., Parish, J.L. The human papillomavirus type 16 L1 protein interacts with E2 and enhances E2-dependent replication and transcription activation. (2015) Journal of General Virology. 96, 2274-2285.
3. Harris, L., McFarlane, L., Campos Leon, K., Roberts, S. and Parish, J.L. The cellular DNA helicase ChlR1 regulates chromatin and nuclear matrix attachment of the human papillomavirus type 16 E2 protein and high copy viral genome establishment: ChlR1 regulates the chromatin association of HPV16 E2. (2017) Journal of Virology. 91(1):1-16. doi: 10.1128/JVI.01853-16.
4. Campos Leon, K., Wijendra, K., Siddiqa, A., Pentland, I., Feeney, K., Knapman, A., Davies, R., Androphy, E. and Parish, J.L. Association of human papillomavirus type 16 E2 with Rad50-interacting protein 1 enhances viral DNA replication: Rint1 participates in HPV DNA replication. (2017) Journal of Virology. 91(5). e02305-16. doi: 10.1128/JVI.02305-16