G1/S Boundary Activates Interferon and Inflammatory Response Genes

Interferons (IFNs) have various roles in antiviral immunity, including curbing the immune system to prevent tissue damage and stimulating adaptive immunity. Due to its protective and destructive properties, IFN expression is tightly regulated. In contrast to its tight regulatory control, IFN expression is highly heterogeneous across many cell types upon pathogenic stimulus. The basis for this heterogenous IFN expression remains incompletely understood. Using single cell RNA-sequencing upon viral infection, we found that interferon expression is upregulated specifically in the late G1 phase of the cell cycle, and cell synchronization at the G1/S boundary boosts interferon expression. Furthermore, cell cycle arrest without any additional stimulus is sufficient to upregulate interferons and hundreds of other inflammatory response genes. Interferon upregulation at the G1/S boundary is cell type specific and not observed in non-immune cell types. Finally, we use ATAC-seq to identify potential transcription factors orchestrating this response. Together, these results uncover the cell cycle as a critical regulator of IFN expression in immune cells.