Epigenetic and transcriptional control of interferon-β

Abstract

The three classes of interferons (IFNs) share the ability to inhibit viral replication, activating cell transcriptional programs that regulate both innate and adaptive responses to viral and intracellular bacterial challenge. Due to their unique potency in regulating viral replication, and their association with numerous autoimmune diseases, the tightly orchestrated transcriptional regulation of IFNs has long been a subject of intense investigation. The protective role of early robust IFN responses in the context of infection with SARS-CoV-2 has further underscored the relevance of these pathways. In this viewpoint, rather than focusing on the downstream effects of IFN signaling (which have been extensively reviewed elsewhere), we will summarize the historical and current understanding of the stepwise assembly and function of factors that regulate IFNβ enhancer activity (the "enhanceosome") and highlight opportunities for deeper understanding of the transcriptional control of the ifnb gene.

Figure 1.

A link between DNAme and IFNβ enhanceosome regulation. After viral sensing, maintenance of UHRF1/DNMT1-mediated methylation of the +1 nucleosome is lost (1), and subsequent NF-κB binding and DNAme removal (2) allows for the binding of IRF3 and cJUN/AFT2 enhanceosome recruitment (3/4). SWI/SNF moves the +1 nucleosome 36 bp downstream, opening up access of Pol-II to TATA box and subsequent transcriptional elongation (5).