WMS-SLS Micro Seminar: Epigenetic regulation of differentiation-dependent HPV gene expression, Dr Jo Parish, Institute of Cancer and Genomic Sciences, College of Medical & Dental Sciences, University of Birmingham
Abstract: Oncogenic human papillomavirus (HPV) infection causes cancers of the anogenital and oropharyngeal tracts. HPV targets the undifferentiated basal cells of the epithelium at these body sites and uses the cellular DNA replication machinery to support virus replication. Viral gene expression in undifferentiated basal cells is attenuated, presumably as part of an immune evasion strategy to ensure persistence of infection. In normal, uninfected epithelia upwards cellular migration induces differentiation and cell cycle exit. However, in HPV-infected cells, differentiation results in increased transcription of the viral oncogenes, E6 and E7, to prevent cell cycle exit and support amplification of the viral DNA. Using a physiological organotypic model of the complex HPV18 life cycle, we have shown that the cellular transcriptional regulators CTCF and YY1 are recruited to the HPV genome to coordinate the formation of an epigenetically repressed chromatin loop between the viral transcriptional enhancer and the early gene region to attenuate early gene expression in undifferentiated cells. Cellular differentiation results in reduced YY1 protein expression and loss of recruitment to the viral genome causing loss of chromatin loop formation, epigenetic de-repression of the viral genome, and enhanced viral early gene expression. The strict control of HPV gene expression combined with manipulation of the host cell environment is vital for persistence of infection and completion of the virus life cycle. Disruption of HPV transcriptional control is also a key step in the development of cancer and we aim to determine the molecular basis for aberrant HPV oncogene expression and identify key events that drive carcinogenesis.
Biography: Dr Jo Parish was awarded a Royal Society University Research Fellowship in 2007 and was appointed Senior Lecturer in Institute of Cancer and Genomic Sciences at the University of Birmingham in 2012.
The main focus of Jo’s research is the study of novel virus-host interactions that are important for viral pathogenesis and persistence. Jo has a longstanding interest in the molecular biology of human papillomavirus (HPV) life cycle and uses state-of-the art model systems and technologies to study HPV replication, persistence and transcriptional control.