SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry

John Kee, Samuel Thudium, David M. Renner, Karl Glastad, Katherine Palozola, Zhen Zhang, Yize Li, Yemin Lan, Joseph Cesare, Andrey Poleshko, Anna A. Kiseleva, Rachel Truitt, Fabian L. Cardenas-Diaz, Xianwen Zhang, Xuping Xie, Darrell N. Kotton, Konstantinos D. Alysandratos, Jonathan A. Epstein, Pei-Yong Shi, Wenli Yang, Edward Morrisey, Benjamin A. Garcia, Shelley L. Berger, Susan R. Weiss and Erica Korb ()
Additional contact information
John Kee: Department of Genetics at the Perelman School of Medicine at the University of Pennsylvania
Samuel Thudium: Department of Genetics at the Perelman School of Medicine at the University of Pennsylvania
David M. Renner: Department of Microbiology at the Perelman School of Medicine at the University of Pennsylvania
Karl Glastad: Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania
Katherine Palozola: Department of Genetics at the Perelman School of Medicine at the University of Pennsylvania
Zhen Zhang: Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania
Yize Li: Department of Microbiology at the Perelman School of Medicine at the University of Pennsylvania
Yemin Lan: Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania
Joseph Cesare: Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania
Andrey Poleshko: Department of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania
Anna A. Kiseleva: Department of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania
Rachel Truitt: Department of Medicine at the Perelman School of Medicine at the University of Pennsylvania
Fabian L. Cardenas-Diaz: Department of Medicine at the Perelman School of Medicine at the University of Pennsylvania
Xianwen Zhang: University of Texas Medical Branch
Xuping Xie: University of Texas Medical Branch
Darrell N. Kotton: Boston University and Boston Medical Center
Konstantinos D. Alysandratos: Boston University and Boston Medical Center
Jonathan A. Epstein: Department of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania
Pei-Yong Shi: University of Texas Medical Branch
Wenli Yang: Department of Medicine at the Perelman School of Medicine at the University of Pennsylvania
Edward Morrisey: Department of Medicine at the Perelman School of Medicine at the University of Pennsylvania
Benjamin A. Garcia: Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania
Shelley L. Berger: Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania
Susan R. Weiss: Department of Microbiology at the Perelman School of Medicine at the University of Pennsylvania
Erica Korb: Department of Genetics at the Perelman School of Medicine at the University of Pennsylvania

Nature, 2022, vol. 610, issue 7931, 381-388

Abstract: Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses1–3. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins4–8, particularly those containing post-translational modifications required for transcriptional regulation9–11. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation12–14. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.

Date: 2022
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DOI: 10.1038/s41586-022-05282-z

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