A nucleosome switch primes hepatitis B virus infection

Nicholas A. Prescott; Tracy Biaco; Andrés Mansisidor; Yaron Bram; Justin Rendleman; Sarah C. Faulkner; Abigail A. Lemmon; Christine Lim; Rachel Tiersky; Eralda Salataj; Liliana Garcia-Martinez; Rodrigo L. Borges; Lluis Morey; Pierre Jacques Hamard; Richard P. Koche; Viviana I. Risca; Robert E. Schwartz; Yael David

doi:10.1016/j.cell.2025.01.033

A nucleosome switch primes hepatitis B virus infection

Nicholas A. Prescott, Tracy Biaco, Andrés Mansisidor, Yaron Bram, Justin Rendleman, Sarah C. Faulkner, Abigail A. Lemmon, Christine Lim, Rachel Tiersky, Eralda Salataj, Liliana Garcia-Martinez, Rodrigo L. Borges, Lluis Morey, Pierre Jacques Hamard, Richard P. Koche, Viviana I. Risca, Robert E. Schwartz, Yael David

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

1 Scopus citations

Abstract

Chronic hepatitis B virus (HBV) infection is an incurable pathogen responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, the Smc5/6 complex. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. By establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA regulates X transcription. We corroborated these findings in situ and further showed that the chromatin-destabilizing molecule CBL137 inhibits full-length X transcription and HBV infection in primary human hepatocytes. Our results shed light on a long-standing paradox and represent a potential therapeutic approach for the treatment of chronic HBV infection.

Original language	English
Pages (from-to)	2111-2126.e21
Journal	Cell
Volume	188
Issue number	8
DOIs	https://doi.org/10.1016/j.cell.2025.01.033
State	Published - 17 Apr 2025
Externally published	Yes

Keywords

chromatin
epigenetics
hepatitis B virus
nucleosome stability
transcription

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10.1016/j.cell.2025.01.033

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Prescott, N. A., Biaco, T., Mansisidor, A., Bram, Y., Rendleman, J., Faulkner, S. C., Lemmon, A. A., Lim, C., Tiersky, R., Salataj, E., Garcia-Martinez, L., Borges, R. L., Morey, L., Hamard, P. J., Koche, R. P., Risca, V. I., Schwartz, R. E., & David, Y. (2025). A nucleosome switch primes hepatitis B virus infection. Cell, 188(8), 2111-2126.e21. https://doi.org/10.1016/j.cell.2025.01.033

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abstract = "Chronic hepatitis B virus (HBV) infection is an incurable pathogen responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, the Smc5/6 complex. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. By establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA regulates X transcription. We corroborated these findings in situ and further showed that the chromatin-destabilizing molecule CBL137 inhibits full-length X transcription and HBV infection in primary human hepatocytes. Our results shed light on a long-standing paradox and represent a potential therapeutic approach for the treatment of chronic HBV infection.",

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AU - Prescott, Nicholas A.

AU - Biaco, Tracy

AU - Mansisidor, Andrés

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AU - Rendleman, Justin

AU - Faulkner, Sarah C.

AU - Lemmon, Abigail A.

AU - Lim, Christine

AU - Tiersky, Rachel

AU - Salataj, Eralda

AU - Garcia-Martinez, Liliana

AU - Borges, Rodrigo L.

AU - Morey, Lluis

AU - Hamard, Pierre Jacques

AU - Koche, Richard P.

AU - Risca, Viviana I.

AU - Schwartz, Robert E.

AU - David, Yael

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Y1 - 2025/4/17

N2 - Chronic hepatitis B virus (HBV) infection is an incurable pathogen responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, the Smc5/6 complex. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. By establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA regulates X transcription. We corroborated these findings in situ and further showed that the chromatin-destabilizing molecule CBL137 inhibits full-length X transcription and HBV infection in primary human hepatocytes. Our results shed light on a long-standing paradox and represent a potential therapeutic approach for the treatment of chronic HBV infection.

AB - Chronic hepatitis B virus (HBV) infection is an incurable pathogen responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, the Smc5/6 complex. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. By establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA regulates X transcription. We corroborated these findings in situ and further showed that the chromatin-destabilizing molecule CBL137 inhibits full-length X transcription and HBV infection in primary human hepatocytes. Our results shed light on a long-standing paradox and represent a potential therapeutic approach for the treatment of chronic HBV infection.

KW - chromatin

KW - epigenetics

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KW - transcription

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VL - 188

SP - 2111-2126.e21

JO - Cell

JF - Cell

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A nucleosome switch primes hepatitis B virus infection

Abstract

Keywords

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