Evasion of antiviral innate immunity by SARS-CoV-2 NSP1 is exerted through H3K9 di-methylation

The pathogen causing the current COVID-19 pandemic, the severe acute respiratory syndrome coronavirus (SARS-CoV-2), evades the innate immune machinery through the independent action of several viral proteins, including the nonstructural protein 1 (NSP1). NSP1 has multiple functions, but the relative contribution of NSP1-mediated translational repression, ribosome-proximate degradation of host mRNA, or other molecular mechanisms to viral immune evasion remains unclear. Here we combined several genome wide approaches, including RNA-seq, ribosome footprinting, and ChIP-seq to find that NSP1 predominantly affects transcription of immune-related genes. NSP1 expression in A549 cells induced Histone 3 Lysine 9 (H3K9) methylation of antiviral gene loci, leading to specific suppression of type I and type III interferon pathways. Treatment with the G9a/GLP H3K9 methyltransferase inhibitor UNC0638 reverses this suppression of antiviral genes and blocks viral replication after SARS-CoV2 infection of A549 cells. Our results call attention to epigenetic reprogramming induced by SARS-CoV2 and highlight the importance to identify innate factors regulating histone modification of gene loci targeted by SARS-CoV-2, with possible relevance to the understanding and therapy of other immunomodulatory diseases. Herin several high throughput approaches including total RNA-Seq, Ribosome footprinting and ChIP-seq are combined to probe NSP1 function. Our results lead us to propose that NSP1 is a multifunctional protein that promotes innate antiviral immune evasion by inducing H3K9 dimethylation. Treatment with the specific H3K9 methyltransferases inhibitor UNC0638 attenuated suppression of antiviral genes by NSP1. In addition, UNC0638 treatment restored antiviral gene expression and blocked viral replication during SARS-CoV2 infection of human lung epithelial cells.