Virology

Biography

Biography: Kewal Krishan Maudar

Abstract

Occult viral hepatitis is a complex clinical entity and is often associated with increased risk of hepato-cellular carcinoma (HCC), one of the main causes of cancer-related deaths worldwide. It is believed that disruption of epigenetic machinery is a vital step towards developing HCC. Although, viral replication differentially affects host genomic integrity in the occult and active disease forms, probable consequence on mitochondrial redox mediated epigenetic regulation still remains to be elucidated. In our earlier studies we demonstrated that occult hepatitis elicits a PI3 kinase mediated DNA damage response. We further aimed to establish a molecular link between virus induced mitochondrial stress and redox mediated epigenetic regulation among occult hepatitis patients. To test this notion, we performed a comprehensive epigenetic analysis on host liver biopsies obtained from occult hepatitis B and C patients (n=10). Prior to biopsy blood samples were also obtained to analyze the levels of mitochondrial oxidative stress. The results observed herein suggested that in spite of low viral load both occult hepatitis B & C viral infections lead to impaired mitochondrial redox signaling and perturbed epigenetic machinery. Higher levels of 8-oxo-dG and reduced mtDNA copy number suggested functional disruption of mitochondrial assembly among occult HBV/HCV infected patients. While epigenetic perturbations in occult hepatitis patients were indicated by distorted histone patterns. We observed a dispersed lysine methylation patterns of monomethylated H4K20 (H4K20me3) and H3K9 (H3K9me1) histones, widely known to distinctly mark silent chromatin regions within the mammalian epigenome. Our study also reported that histone H3 and H2A other vital histone, often associated with chromatin condensation and regulation underwent significant modifications in the form of phosphorylation at Ser-10 (phospho-H3) and ubiquitination as uH2A, respectively. Taken together, our study provides novel insights of deregulated ‘histone code’ dynamics in occult hepatitis B/C patients that might play as an intermediate step for development and progression of HCC among these patients. It also showcases inextricable role of virus induced mitochondrial stress and epigenomic imbalance which may be helpful in identifying novel therapeutic targets for effective virus removal in occult states.