An atlas of the human liver diurnal transcriptome and its perturbation by hepatitis C virus infection

Atish Mukherji, Frank Jühling, Yogy Simanjuntak, Emilie Crouchet, Fabio Zompo, Yuji Teraoka, Alexandre Haller, Philippe Baltzinger, Soumith Paritala, Fahmida Rasha, Naoto Fujiwara, Cloé Gadenne, Nevena Slovic, Marine A. Oudot, Sarah C. Durand, Clara Ponsolles, Catherine Schuster, Xiaodong Zhuang, Jacinta Holmes, Ming-Lun Yeh, Hiromi Abe-Chayama, Mathias Heikenwälder, Angelo Sangiovanni, Massimo Iavarone, Massimo Colombo, Steven K. H. Foung, Jane A. McKeating, Irwin Davidson, Ming-Lung Yu, Raymond T. Chung, Yujin Hoshida, Kazuaki Chayama, Joachim Lupberger () and Thomas F. Baumert ()
Additional contact information
Atish Mukherji: Institute of Translational Medicine and Liver Diseases (ITM)
Frank Jühling: Institute of Translational Medicine and Liver Diseases (ITM)
Yogy Simanjuntak: Institute of Translational Medicine and Liver Diseases (ITM)
Emilie Crouchet: Institute of Translational Medicine and Liver Diseases (ITM)
Fabio Zompo: Institute of Translational Medicine and Liver Diseases (ITM)
Yuji Teraoka: National Hospital Organization Kure Medical Center
Alexandre Haller: CNRS/INSERM/University of Strasbourg
Philippe Baltzinger: CNRS/INSERM/University of Strasbourg
Soumith Paritala: University of Texas Southwestern Medical Center
Fahmida Rasha: University of Texas Southwestern Medical Center
Naoto Fujiwara: University of Texas Southwestern Medical Center
Cloé Gadenne: Institute of Translational Medicine and Liver Diseases (ITM)
Nevena Slovic: Institute of Translational Medicine and Liver Diseases (ITM)
Marine A. Oudot: Institute of Translational Medicine and Liver Diseases (ITM)
Sarah C. Durand: Institute of Translational Medicine and Liver Diseases (ITM)
Clara Ponsolles: Institute of Translational Medicine and Liver Diseases (ITM)
Catherine Schuster: Institute of Translational Medicine and Liver Diseases (ITM)
Xiaodong Zhuang: University of Oxford
Jacinta Holmes: St Vincent’s Hospital
Ming-Lun Yeh: Kaohsiung Medical University
Hiromi Abe-Chayama: Center for Medical Specialist Graduate Education and Research, Hiroshima University
Mathias Heikenwälder: German Cancer Research Center (DKFZ)
Angelo Sangiovanni: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Massimo Iavarone: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Massimo Colombo: EASL International Liver Foundation
Steven K. H. Foung: Stanford University School of Medicine
Jane A. McKeating: University of Oxford
Irwin Davidson: CNRS/INSERM/University of Strasbourg
Ming-Lung Yu: Kaohsiung Medical University
Raymond T. Chung: Massachusetts General Hospital
Yujin Hoshida: University of Texas Southwestern Medical Center
Kazuaki Chayama: RIKEN Center for Integrative Medical Sciences
Joachim Lupberger: Institute of Translational Medicine and Liver Diseases (ITM)
Thomas F. Baumert: Institute of Translational Medicine and Liver Diseases (ITM)

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51698-8

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