Loss of CTCF-YY1-mediated regulation of human papillomavirus oncogene transcription in HPV-driven disease

Burley, Megan (2023). Loss of CTCF-YY1-mediated regulation of human papillomavirus oncogene transcription in HPV-driven disease. University of Birmingham. Ph.D.

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Abstract

Persistent human papillomavirus (HPV) infection is a risk factor for oropharyngeal squamous cell carcinoma (OPSCC). The viral oncogenes E6 and E7 drive cell growth and delay differentiation. Expression of E6/E7 is tightly regulated during the HPV life cycle. In basal keratinocytes, the CCCTC-binding factor (CTCF) binds the HPV18 episome at the E2 open reading frame to mediate the formation of an epigenetically repressed chromatin loop through association with Yin Yang 1 (YY1) bound at the viral enhancer. Following differentiation, depletion in YY1 results in chromatin remodelling and increased transcription. As such, YY1 is a key mediator of differentiation dependent depression of HPV oncogene transcription. Whilst CTCF-YY1-mediated chromatin looping is essential in regulating early gene expression during the HPV life cycle, it is unclear whether this mechanism of transcription control is deregulated during carcinogenesis. Using physiological models of HPV-induced disease and OPSCC cell lines we show a switch in YY1 function from transcriptional repression to transactivation of the HPV early promoter. YY1 enrichment at the viral enhancer becomes significantly increased during disease progression which is coincident with open chromatin and high E6/E7 expression. We show a robust enrichment of active histone modifications histone H3 acetylation (H3K27Ac) and histone H4 methylation (H3K4me3) when YY1 is bound. Following depletion of YY1 we see a significant reduction in E6/E7 expression as a result of reduced chromatin accessibility at the viral enhancer. Interestingly, in the context of transcriptional regulation, CTCF appears to be redundant within OPSCCs where it exerts no effect on E6/E7 transcription. Overall, we describe a mechanism in which YY1 functions to drive the overexpression of E6 and E7 during the progression of HPV-driven oropharyngeal carcinomas.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):