Although tumours initiate from oncogenic changes in a cancer cell, subsequent tumour progression and therapeutic response depend on interactions between the cancer cells and the tumour microenvironment (TME). The primary monocilium, or cilium, provides a spatially localized platform for signalling by Hedgehog, Notch, WNT and some receptor tyrosine kinase pathways and mechanosensation. Changes in ciliation of cancer cells and/or cells of the TME during tumour development enforce asymmetric intercellular signalling in the TME. Growing evidence indicates that some oncogenic signalling pathways as well as some targeted anticancer therapies induce ciliation, while others repress it. The links between the genomic profile of cancer cells, drug treatment and ciliary signalling in the TME likely affect tumour growth and therapeutic response.

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 responses 1 – 3 . In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins 4 – 8 , particularly those containing post-translational modifications required for transcriptional regulation 9 – 11 . Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation 12 – 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.