A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor

Carla Eller; Laura Heydmann; Che C. Colpitts; Houssein El Saghire; Federica Piccioni; Frank Jühling; Karim Majzoub; Caroline Pons; Charlotte Bach; Julie Lucifora; Joachim Lupberger; Michael Nassal; Glenn S. Cowley; Naoto Fujiwara; Sen Yung Hsieh; Yujin Hoshida; Emanuele Felli; Patrick Pessaux; Camille Sureau; Catherine Schuster; David E. Root; Eloi R. Verrier; Thomas F. Baumert

doi:10.1038/s41467-020-16517-w

A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor

Carla Eller, Laura Heydmann, Che C. Colpitts, Houssein El Saghire, Federica Piccioni, Frank Jühling, Karim Majzoub, Caroline Pons, Charlotte Bach, Julie Lucifora, Joachim Lupberger, Michael Nassal, Glenn S. Cowley, Naoto Fujiwara, Sen Yung Hsieh, Yujin Hoshida, Emanuele Felli, Patrick Pessaux, Camille Sureau, Catherine SchusterDavid E. Root, Eloi R. Verrier, Thomas F. Baumert

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle.

Original language	English (US)
Article number	2707
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16517-w
State	Published - Dec 1 2020
Externally published	Yes

ASJC Scopus subject areas

General
Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Eller, C., Heydmann, L., Colpitts, C. C., El Saghire, H., Piccioni, F., Jühling, F., Majzoub, K., Pons, C., Bach, C., Lucifora, J., Lupberger, J., Nassal, M., Cowley, G. S., Fujiwara, N., Hsieh, S. Y., Hoshida, Y., Felli, E., Pessaux, P., Sureau, C., ... Baumert, T. F. (2020). A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor. Nature communications, 11(1), Article 2707. https://doi.org/10.1038/s41467-020-16517-w

Eller, C, Heydmann, L, Colpitts, CC, El Saghire, H, Piccioni, F, Jühling, F, Majzoub, K, Pons, C, Bach, C, Lucifora, J, Lupberger, J, Nassal, M, Cowley, GS, Fujiwara, N, Hsieh, SY, Hoshida, Y, Felli, E, Pessaux, P, Sureau, C, Schuster, C, Root, DE, Verrier, ER & Baumert, TF 2020, 'A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor', Nature communications, vol. 11, no. 1, 2707. https://doi.org/10.1038/s41467-020-16517-w

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title = "A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor",

abstract = "Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle.",

author = "Carla Eller and Laura Heydmann and Colpitts, {Che C.} and {El Saghire}, Houssein and Federica Piccioni and Frank J{\"u}hling and Karim Majzoub and Caroline Pons and Charlotte Bach and Julie Lucifora and Joachim Lupberger and Michael Nassal and Cowley, {Glenn S.} and Naoto Fujiwara and Hsieh, {Sen Yung} and Yujin Hoshida and Emanuele Felli and Patrick Pessaux and Camille Sureau and Catherine Schuster and Root, {David E.} and Verrier, {Eloi R.} and Baumert, {Thomas F.}",

note = "Funding Information: We thank Claudine Ebel, Romain Kaiser, and Muriel Phillips (IGBMC, Flow Cytometry platform, France) for excellent technical assistance. We thank Christelle Thibault for the microarray analysis (IGBMC, GenomEast platform, Illkirch, France). We thank our colleague Sarah Durand (U1110) for the excellent technical support. This work was supported by Inserm, the University of Strasbourg, the European Union (ERC-2014-AdG-671231-HEPCIR, Infect-ERA hepBccc, EU H2020 Hep-CAR 667273), the IHU Fondation ARC (French Cancer Agency) TheraHCC program IHU201301187 and IHU201901299, the Institut Universitaire de France and the Agence Nationale de Recherche sur le Sida et les h{\'e}patites virales (ANRS) and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R03AI131066. C.C.C. acknowledges fellowships from the Canadian Institutes of Health Research (201411MFE-338606-245517) and the Canadian Network on Hepatitis C. E.R.V. acknowledges fellowship from ANRS (ECTZ50121). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41467-020-16517-w",

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T1 - A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor

AU - Eller, Carla

AU - Heydmann, Laura

AU - Colpitts, Che C.

AU - El Saghire, Houssein

AU - Piccioni, Federica

AU - Jühling, Frank

AU - Majzoub, Karim

AU - Pons, Caroline

AU - Bach, Charlotte

AU - Lucifora, Julie

AU - Lupberger, Joachim

AU - Nassal, Michael

AU - Cowley, Glenn S.

AU - Fujiwara, Naoto

AU - Hsieh, Sen Yung

AU - Hoshida, Yujin

AU - Felli, Emanuele

AU - Pessaux, Patrick

AU - Sureau, Camille

AU - Schuster, Catherine

AU - Root, David E.

AU - Verrier, Eloi R.

AU - Baumert, Thomas F.

N1 - Funding Information: We thank Claudine Ebel, Romain Kaiser, and Muriel Phillips (IGBMC, Flow Cytometry platform, France) for excellent technical assistance. We thank Christelle Thibault for the microarray analysis (IGBMC, GenomEast platform, Illkirch, France). We thank our colleague Sarah Durand (U1110) for the excellent technical support. This work was supported by Inserm, the University of Strasbourg, the European Union (ERC-2014-AdG-671231-HEPCIR, Infect-ERA hepBccc, EU H2020 Hep-CAR 667273), the IHU Fondation ARC (French Cancer Agency) TheraHCC program IHU201301187 and IHU201901299, the Institut Universitaire de France and the Agence Nationale de Recherche sur le Sida et les hépatites virales (ANRS) and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R03AI131066. C.C.C. acknowledges fellowships from the Canadian Institutes of Health Research (201411MFE-338606-245517) and the Canadian Network on Hepatitis C. E.R.V. acknowledges fellowship from ANRS (ECTZ50121). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

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N2 - Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle.

AB - Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle.

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A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor

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