Despite an efficient antiviral therapy, chronic Hepatitis C virus infection (CHC) and associated liver complications remain being an important global health burden. CHC perturbs liver functions by causing chronic inflammation, metabolic disorder, fibrosis, and hepatocellular carcinoma (HCC). The liver is a highly circadian organ with precisely timed physiologic functions throughout the day. While well studied in rodent models, our understanding of the rhythmic expression of genes (regulated by the circadian clock) in human disease is still evolving.
A rhythmic symphony of genes
To identify rhythmic transcriptome and epigenome of human hepatocytes, the study used human liver chimeric mice. This unique model allows the study human liver tissue in a living animal, providing valuable insights into the natural behaviour of human cells. Using advanced bioinformatic algorithms the analyses identified a vast array of rhythmically expressed protein-coding genes, including key transcription factors and chromatin modifiers, which are important regulators of liver homeostasis.
The viral hijack: HCV’s disruption of rhythmic pathways
The study revealed that liver pathogens like HCV infection perturb the hepatic transcriptome. By altering the rhythmicity of over 1000 genes, HCV disrupts the regulation of gene expression, leading to a cascade of downstream effects. Moreover, HCV infection of human hepatocytes also impacts the epigenome on the level of chemical histone modifications that influence gene activity. The study revealed that HCV-associated epigenetic disruption activates critical pathways involved in metabolic alterations, fibrosis, and ultimately, cancer.
Clinical Implications and Future Directions
The findings of the study have profound clinical implications. By understanding how HCV perturbs the hepatic rhythmic pathways, we can gain valuable insights into the mechanisms underlying cancer development. This knowledge may pave the way for the development of novel biomarkers and therapeutic strategies aimed at predicting the risk of disease progression and preventing liver cancer development in patients at elevated risk and thus lead to novel tools for better diagnosis and personalized treatments.
Conclusion
The findings of this study identified a novel, previously unrecognized way by which HCV infection causes liver disease progression towards cancer. By unravelling the complex interplay between the virus and the liver’s internal clock, we have taken a significant step towards understanding the pathogenesis of this disease. These findings offer promising avenues for future research and clinical applications, ultimately improving the lives of patients affected by HCV-related liver disease.
Out of sync: HCV-disrupted transcriptional oscillation is a driver of liver disease and cancer
