慢性肝病和癌症是全球健康挑战。生物钟作为肝脏生理和疾病调节剂的作用在啮齿类动物中已得到很好的证实，然而，人类疾病中节律表达基因的身份和表观遗传调节的研究还较少。在这里，我们使用雄性人肝嵌合小鼠揭示了人肝细胞的节律转录组和表观基因组。我们在雄性嵌合小鼠的人肝细胞中鉴定了大量有节律表达的蛋白质编码基因，其中包括关键转录因子、染色质修饰剂和关键酶。我们发现，丙型肝炎病毒 (HCV) 感染是肝病和癌症的主要原因，它通过改变 1000 多个基因的表达节律来扰乱转录组，并影响表观基因组，从而激活介导代谢的关键途径。改变、纤维化和癌症。在晚期肝病患者中，HCV 扰乱的节律通路仍然失调。总的来说，这些数据支持病毒引起的肝节律转录组扰动和癌症发展中的通路的作用，并可能为癌症预防和生物标志物预测 HCC 风险提供机会。© 2024。作者。

Chronic liver disease and cancer are global health challenges. The role of the circadian clock as a regulator of liver physiology and disease is well established in rodents, however, the identity and epigenetic regulation of rhythmically expressed genes in human disease is less well studied. Here we unravel the rhythmic transcriptome and epigenome of human hepatocytes using male human liver chimeric mice. We identify a large number of rhythmically expressed protein coding genes in human hepatocytes of male chimeric mice, which includes key transcription factors, chromatin modifiers, and critical enzymes. We show that hepatitis C virus (HCV) infection, a major cause of liver disease and cancer, perturbs the transcriptome by altering the rhythmicity of the expression of more than 1000 genes, and affects the epigenome, leading to an activation of critical pathways mediating metabolic alterations, fibrosis, and cancer. HCV-perturbed rhythmic pathways remain dysregulated in patients with advanced liver disease. Collectively, these data support a role for virus-induced perturbation of the hepatic rhythmic transcriptome and pathways in cancer development and may provide opportunities for cancer prevention and biomarkers to predict HCC risk.© 2024. The Author(s).