THE INTERPLAY BETWEEN HEPATITIS C VIRUS INFECTION, CHANGES IN HIGHER ORDER CHROMATIN ORGANIZATION AND CANCER

Hepatitis C virus (HCV) infection is the leading cause of chronic hepatitis which often results in liver fibrosis, cirrhosis and Hepatocellular carcinoma (HCC). Infection of liver cells by HCV has been shown to modify fundamental cell process including transcription. However, the molecular pathways governing these effects and their impact on tumorigenesis are poorly understood. In recent years, long range chromatin interactions (LRCI), have been recognized as major factors in chromosome stability and dynamics and regulation of gene expression. We aim to understand the interplay between HCV infection and changes in higher order chromatin interactions. Chromosom spreads reveal a striking phenotype of smaller chromosomes and hyper condensation in HCV-infecetd cells compared to non infcted cells. This observation may be explained by the higher levels of proteins that regulets LRCI at the nucleus of prometaphase infected cells that may influence chromatin compaction. Moreover, HCV infected cells frequently assembled multipolar spindles in early mitosis that may lead to uneuploidy, a phenotype that is associated with miregulation of level and function of the LRCI regulating protein cohesin. By chromatin immunoprcipitation followed by next generation sequencing (ChIP-seq) we show that the infection influences the positioning of the cohesin subunit Rad21 on the chromatin. Integration of ChIP-seq analysis with transcriptome analysis points for role of LRCI proteins in regulating gene expression that are implicated in oncogenesis. Thus, this study unravels a novel link between HCV induced changes in LRCI and HCC through affecting gene expression and chromosomal stability.