Elucidating the role of CTCF in the control of hepatitis B virus gene expression

Research Link: http://www.birmingham.ac.uk/staff/profiles/cancer-genomic/parish-jo.aspx
Enquires are encouraged by email to Dr. J Parish; [Email Address Removed]

Hepatitis B virus (HBV) is one of the world’s last unconquered infections, with 270 million infected subjects. HBV replicates in the liver and infection results in progressive liver disease, cirrhosis and hepatocellular carcinoma (HCC). Although current therapies reduce viral replication and associated-liver disease they rarely cure infection, highlighting the urgent need for new strategies to eradicate HBV.

As obligate parasites viruses have evolved to manipulate their host to their advantage. However, our understanding of the host pathways regulating HBV transcription, protein expression and replication has been hampered due to the limited permissivity of in vitro culture systems. The recent discovery that sodium taurocholate co-transporting polypeptide (NTCP)1 is a receptor for HBV has revolutionized in vitro culture systems to study HBV replication. Using this new model system, our research group is focussing on understanding the mechanistic control of HBV gene expression. Since viruses target important cellular pathways for efficient life cycle completion, understanding the manipulation of cellular transcription regulation complexes by the virus will allow us to understand fundamental cellular mechanisms of transcription regulation.

CCCTC-binding factor (CTCF) is a ubiquitously expressed host architectural protein that binds specific sites within the human genome and controls numerous genomic processes, including transcriptional repression and activation, genetic imprinting, chromatin insulation and gene splicing2. CTCF is a key regulator of the life cycle of a number of clinically relevant, cancer-causing viruses including Epstein Barr virus, Kaposi’s sarcoma-associated herpesvirus and human papillomavirus (HPV)4. Our work in HPV has shown that CTCF regulates viral oncogene expression by controlling the activity of the viral promoter and regulating splicing of viral transcripts3. Following on from these studies, we have demonstrated that CTCF co-ordinates 3-dimensional loop formation in the HPV genome, which is vital for the transcriptional regulation of the viral promoter (Pentland and Parish, manuscript in preparation).

We have recently demonstrated that CTCF as an important regulator of the HBV X-promoter, which controls the expression of the oncogenic HBx protein. Understanding how HBx expression is regulated is therefore both biologically and clinically important. We have mapped a CTCF binding site within the HBx promoter and shown that CTCF activates this promoter using in vitro transcription assays. However, the downstream consequences of CTCF-mediated regulation of HBx protein expression is unknown.

This project will elucidate CTCF function in the control of HBx transcription through epigenetic regulation and/or the formation of three-dimensional loops within HBV episomes. We will also determine CTCF function in the control of HBV transcript splicing and in the persistent replication of HBV genomes in infected cells.

HOW TO APPLY
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2. Notify MIBTP of your application by completing an online notification form - http://www2.warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/submission/