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

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.

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Publication Details

Journal
Nature Communications
Published
2024-08-29
DOI
https://doi.org/10.1038/s41467-024-51698-8
Citations
12
Primary Topic
Epigenetics and DNA Methylation
Type
article
Field-Weighted Citation Impact
2.81

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article

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

Clara Ponsolles, M. Colombo, Fahmida Rasha, Yujin Hoshida et al.
12 citations
Nature Communications
Epigenetics and DNA Methylation
2.81
article

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

Clara Ponsolles, M. Colombo, Fahmida Rasha, Yujin Hoshida, Thomas F. Baumert, Frank Jühling, Raymond T. Chung, Mathias Heikenwälder, Kazuaki Chayama, Atish Mukherji, Nevena Slovic, Yuji Teraoka, Naoto Fujiwara, Angelo Sangiovanni, Jacinta Alison Holmes, Irwin Davidson, Jane A. McKeating, Catherine Schuster, Cloé Gadenne, Émilie Crouchet, Yogy Simanjuntak, Hiromi Abe‐Chayama, Xiaodong Zhuang, Ming‐Lun Yeh, Marine A. Oudot, Steven K. H. Foung, Joachim Lupberger, Alexandre Haller, Ming‐Lung Yu, Sarah Durand, Philippe Baltzinger, Massimo Alberto Iavarone, Fabio Del Zompo, Soumith Paritala
article en
12 citations

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.

Nature CommunicationsVol. 15(1)
Hiroshima University (JP), Centre National de la Recherche Scientifique (FR), National Sun Yat-sen University (TW), Kaohsiung Medical University (TW), Inserm (FR), The University of Melbourne (AU), German Cancer Research Center (DE), Institut Universitaire de France (FR), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Heidelberg University (DE), Kaohsiung Medical University Chung-Ho Memorial Hospital (TW), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), University of Oxford (GB), Institut de génétique et de biologie moléculaire et cellulaire (FR), St Vincent's Hospital Melbourne (AU), Massachusetts General Hospital (US), Institut de Recherche contre les Cancers de l’Appareil Digestif (FR), National Hospital Organization (JP), Hôpitaux Universitaires de Strasbourg (FR), RIKEN Center for Integrative Medical Sciences (JP), Kure Medical Center (JP), Hôpital Saint-Vincent-de-Paul (FR), Institute for Translational Medicine and Liver Disease (FR), University College London (GB), Université de Strasbourg (FR), University of Tübingen (DE), The University of Texas Southwestern Medical Center (US), Stanford University (US)
National Sun Yat-sen University, Deutsches Krebsforschungszentrum, Japan Agency for Medical Research and Development, Wellcome Trust, European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Sun Yat-sen University, Université de Strasbourg, Fondation ARC pour la Recherche sur le Cancer, Medical Research Council
Good health and well-being
Openalex Percentile: Top 9%
Epigenetics and DNA Methylation
2.81
DOIOpen Access PDFOpenAlex
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