Every avid trick-or-treater aspires to have the perfect Halloween costume; now, a spooky study has revealed how an unwanted guest – SARS-CoV-2 – dons an epigenetic disguise to help this virus trick its way past host defenses to infect human cells!
A fearless team led by Erica Korb (University of Pennsylvania, USA) knew that SARS-CoV-2 could disrupt chromatin by promoting heterochromatin formation, which reduces gene expression to inhibit anti-viral responses. Some viruses carry out this ghoulish act through histone mimicry – viral proteins wear a disguise that makes them resemble the histone proteins that regulate the expression of anti-viral host cell response genes; however, we lacked evidence that coronavirus family member’s use of ominous strategy.
- Bioinformatics analysis reveals a “look-alike” amino acid motif present in the SARS-CoV-2 ORF8 accessory protein that mimics histone H3 protein regions that undergo post-translational modification to regulate gene transcription
- This finding suggests that ORF8 can interfere with H3 function by donning an epigenetic “disguise”
- After infection of HEK293T cells, the ORF8 protein diffuses into the nucleus and interacts with chromatin and H3-containing protein complexes that regulate nuclear (laminin proteins) and chromatin (HP1) structure
- ORF8 ChIP–seq shows binding at genomic regions associated with H3K27me3; however, an ORF8 protein lacking the look-alike motif displays reduced chromatin binding
- The ORF8 look-alike motif undergoes acetylation in a comparable manner to histone H3
- ORF8 expression reduces levels of transcriptionally permissive histone modifications but increases transcriptional repressive histone modifications in target cells, thereby reducing chromatin accessibility measured by ATAC-seq
- This epigenetic effect strictly depends on the presence of the look-alike motif
- Infection by SARS-CoV-2 lacking ORF8 or an ORF8 lacking the look-alike motif does not disrupt host cell chromatin but only has a marginal effect on viral replication in human pulmonary cells compared to wild-type virus
- Differing transcriptional responses to infection between wild-type, Orf8-lacking, and look-alike motif-lacking viruses may indicate the influence of other Orf8 domains on gene transcription
Spooky stuff! These results describe disrupted host cell epigenetic regulation by a SARS-CoV-2 accessory protein wearing an epigenetic disguise as a disease-related mechanism. These data, in combination with a study linking ORF8 deletion to less severe disease, suggest that studies should now focus on how ORF8 alters viral infection/spread and disease development.
Treat yourself to a little more reading to know how to avoid the epigenetic tricks of SARS-CoV-2 over at Nature, October 2022.