Hepatitis B virus and regulation of gene expression
Mechanisms of Transcription Activation in Vivo
The regulation of gene expression is a fundamental aspect of most biological processes and is often affected in disease. We use the yeast Saccharomyces cerevisiae as a model to address fundamental questions about the mechanisms by which transcriptional activators control gene expression. We are particularly interested in understanding how the RNA polymerase II basal transcription machinery assembles at the promoter of genes in response to activators, an in determining the role of chromatin and histone modifications in this process. We found that assembly of the basal machinery is a stepwise event in vivo, and that transcription is accompanied by a highly dynamic exchange of histones in the promoter region. We now wish to explore the role of activators and specific histone chaperones in the dynamics of chromatin and the involvement of this process in transcription and associated epigenetic events.
The HBx Protein of Hepatitis B Virus
Chronic infection by hepatitis B virus (HBV) affects over 350 million people worldwide and is a leading cause of hepatocellular carcinoma, one of the most common cancers in humans. Because current treatments of chronic HBV infection have limited success, new therapeutic strategies are needed. HBV encodes a regulatory protein, known as HBx, which is essential for infection and has been implicated in HBV-mediated liver oncogenesis. The basis for HBx function in either process remains elusive and is the focus of our research studies. Two HBx activities that may be relevant to HBV infection and associated liver cancer are its abilities to enhance HBV replication and to induce genetic instability in cultured cells. We obtained structural, biochemical and genetic evidence that both activities require binding of HBx to host cell protein DDB1, a subunit of an E3 ligase involved in cell cycle regulation. Our current work is aimed at identifying the cellular targets of the HBx-DDB1 complex and further exploring its role under conditions closer to natural HBV infection. Given the likely fundamental importance of the HBx-DDB1 interaction for natural HBV infection and associated liver cancer, this virus-host protein interaction may represent a promising new target for therapeutic intervention.