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SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry.
Kee, John; Thudium, Samuel; Renner, David M; Glastad, Karl; Palozola, Katherine; Zhang, Zhen; Li, Yize; Lan, Yemin; Cesare, Joseph; Poleshko, Andrey; Kiseleva, Anna A; Truitt, Rachel; Cardenas-Diaz, Fabian L; Zhang, Xianwen; Xie, Xuping; Kotton, Darrell N; Alysandratos, Konstantinos D; Epstein, Johnathan A; Shi, Pei-Yong; Yang, Wenli; Morrisey, Edward; Garcia, Benjamin A; Berger, Shelley L; Weiss, Susan R; Korb, Erica.
  • Kee J; Department of Genetics at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Thudium S; Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Renner DM; Department of Genetics at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Glastad K; Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Palozola K; Department of Microbiology at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Zhang Z; Penn Center for Research on Coronaviruses and Other Emerging Pathogens at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Li Y; Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Lan Y; Department of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Cesare J; Department of Genetics at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Poleshko A; Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Kiseleva AA; Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Truitt R; Department of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Cardenas-Diaz FL; Department of Microbiology at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Zhang X; Penn Center for Research on Coronaviruses and Other Emerging Pathogens at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Xie X; Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Kotton DN; Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Alysandratos KD; Department of Biochemistry and Biophysics at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Epstein JA; Department of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Shi PY; Department of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Yang W; Penn Cardiovascular Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Morrisey E; Institute for Regenerative Medicine at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Garcia BA; Department of Medicine at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Berger SL; Department of Medicine at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Weiss SR; Penn-CHOP Lung Biology Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Korb E; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
Nature ; 610(7931): 381-388, 2022 10.
Article in English | MEDLINE | ID: covidwho-2050416
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Viral Proteins / Histones / Molecular Mimicry / Epigenesis, Genetic / Host Microbial Interactions / SARS-CoV-2 / COVID-19 Type of study: Observational study / Prognostic study Limits: Humans Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-022-05282-z

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Viral Proteins / Histones / Molecular Mimicry / Epigenesis, Genetic / Host Microbial Interactions / SARS-CoV-2 / COVID-19 Type of study: Observational study / Prognostic study Limits: Humans Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-022-05282-z