A genome-wide map of the genetic network in monocytes that regulates type I interferon induction by the cGAS-STING pathway

Type I interferons (IFNs) are induced by pattern recognition receptors (PRRs) of the innate immune system to protect against foreign pathogens and malignant transformation, and their production must be tightly regulated to balance antiviral defense with tissue homeostasis. To define the genetic network that governs IFN regulation, we conducted genome-wide CRISPR screens for genes that positively or negatively regulated IFNB1 gene expression induced by the PRR cGAS and its downstream effector STING, in both unprimed THP-1 cells and cells primed with IFN-α to mimic an ongoing inflammatory response. Distinct subsets of genes affected IFNB1 induction in the unprimed and primed states, and many regulators had not previously been associated with IFN responses, thereby linking IFNB1 regulation to various cellular pathways. For example, we found that the NCoR/SMRT corepressor complex components TBL1XR1 and HDAC3 cooperated to support IFNB1 expression, with HDAC3 promoting activation of the kinase TBK1, an essential driver of type I IFN responses. These datasets are a resource for identifying genes associated with type I IFN–related inborn errors of immunity and cancer and for developing therapies to modulate STING signaling in interferonopathies and other conditions of dysregulated type I IFN.