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

Atish Mukherji (1) , Frank Juehling (1) , Yogy Simanjuntak (1) , Emilie Crouchet (1) , Fabio del Zompo (1) , Yuji Teraoka , Alexandre Haller (2) , Philippe Baltzinger (2) , Soumith Paritala (3) , Fahmida Rasha (3) , Naoto Fujiwara (3) , Cloé Gadenne (1) , Nevena Slovic (1) , Marine Oudot (1) , Sarah C. Durand (1) , Clara Ponsolles (1) , Catherine Schuster (1) , Xiaodong Zhuang (4, 5) , Jacinta Holmes (6, 7) , Ming-Lun Yeh (8, 9) , Hiromi Abe-Chayama (10) , Mathias Heikenwälder (11, 12) , Angelo Sangiovanni (13) , Massimo Iavarone (13) , Massimo Colombo (14) , Steven K H Foung (15) , Jane A Mckeating (4) , Irwin Davidson (2) , Ming-Lung Yu (8, 9, 16) , Raymond T Chung (17) , Yujin Hoshida (3) , Kazuaki Chayama (18, 19) , Joachim Lupberger (1) , Thomas F. Baumert (1, 20, 21, 22)

1 ITM - Institute for Translational Medicine and Liver Disease
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
3 University of Texas Southwestern Medical Center [Dallas]
4 University of Oxford
5 UCL - University College of London [London]
6 University of Melbourne
7 St. Vincent's Hospital, Melbourne
8 Kaohsiung Medical University Hospital [Kaohsiung, Taïwan]
9 KMU - Kaohsiung Medical University [Kaohsiung, Taïwan]
10 Hiroshima University
11 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
12 Eberhard Karls Universität Tübingen = University of Tübingen
13 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
14 ILF - EASL International Liver Foundation [Geneva, Switzerland]
15 Stanford University
16 NSYSU - National Sun Yat-sen University
17 Massachusetts General Hospital [Boston]
18 RIKEN IMS - RIKEN Center for Integrative Medical Sciences [Yokohama]
19 Institute of Biomedical & Health Sciences [Hiroshima, Japan]
20 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
21 IUF - Institut universitaire de France
22 IHU Strasbourg - L'Institut hospitalo-universitaire de Strasbourg

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.

Mots clés: metabolism; virology; genetics; physiology

Domaines: Médecine humaine et pathologie

Atish Mukherji, Frank Juehling, Yogy Simanjuntak, Emilie Crouchet, Fabio del Zompo, et al.. An atlas of the human liver diurnal transcriptome and its perturbation by hepatitis C virus infection.. Nature Communications, 2024, 15 (1), pp.7486. ⟨10.1038/s41467-024-51698-8⟩. ⟨hal-04699545⟩