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 Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-020-16517-w

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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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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.",

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AU - Piccioni, Federica

AU - Jühling, Frank

AU - Majzoub, Karim

AU - Pons, Caroline

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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.

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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

Abstract

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