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Impaired Mitochondrial Redox Sinalling Leads to Aberrant Epigenetic Regulation in Occult Hepatitis B & C Infections
Kewal K. Maudar^*
G.I. Surgery and Administration, Bhopal Memorial Hospital & Research Centre, Bhopal, Madhya Pradesh, India

INTRODUCTIONOccult viral hepatitis is often associated with increased risk of hepatocellular carcinoma (HCC). Epigenetic deregulation and mitochondrial dysfunction lead to genomic and epigenomic damage.Present study was aimed to establish a molecular link between virusinduced mitochondrial oxidative stress and redox mediated epigenetic regulation among occult hepatitis patients.METHODSThe study was carried out on patients with occult HBV & HCV,chronic HBV & HCV patients and age and gender matched controls (n=10 each).The cells were fixed, permeabilized and incubated with <span style="line-height:20.8px">anti-H3K9me1, anti-H4K20me3, anti-phospho-H3, anti-ubiquitinated H2A/H2B and anti-phospho-H2AX</span> for different histone modifications.Quantification was done through flow cytometric analysis.Fluorescence tagged immune-stained cells were analyzed for 10000 total events.RESULTS In occult HBV patients, HBV DNA was positive in plasma and peripheral lymphocytes,viral load ranged from 20 to 80 IU/mL. Occult HCV patients were reported to be anti-HCV positive, serum HCV RNA negative, but positive for HCV RNA in peripheral lymphocytes with viral load ranging from 30 to 60 IU/ml. The chronic HBV patients were positive for HBsAg, anti-HBc and HBV DNA and their viral load ranged from 500 to 1000 IU/mL. Chronic HCV patients were positive for anti-HCV and had serum HCV RNA levels ranging from 800 to 1500 IU/ml. The results suggested that desspite low viral load,occult hepatitis B & C 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. Depending on the specific site and degree of methylation within histone sequence, histone lysine methylation correlates with gene expression leading to repression or activation. We observed a dispersed lysine methylation pattern of monomethylated H4K20 and H3K9 histones, widely known to distinctly mark silent chromatin regions within the mammalian epigenome. CONCLUSION The results suggested that in comparison to control cell population the expression pattern of all four core histones altered distinctly in occult patients. Taken together, present study provides novel insights of deregulated ‘histone code’ dynamics in occult hepatitis B/C patients that might play an intermediate step for development and progression of HCC among these patients. The virus induced mitochondrial stress and epigenomic imbalance may provide a breakthrough for prevention and novel therapeutic targets for HCC in occult HBV and HCV infections.

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