The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity [RNA-seq]

The regulation of proper gene transcription is critical for anti-viral defense. Dynamics of enhancer activity play important roles in many biological processes, and epigenomic analysis is widely used to determine the involved enhancers and transcription factors. To determine new transcription factors in anti-DNA-virus response, we perform H3K27ac ChIP-Seq analysis to profile the active enhancer pattern in HSV-1-infected THP-1 cells. We have identified three transcription factors, NR2F6, MEF2D and MAFF, and experimentally verified their roles in promoting HSV-1 replication. NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, which is not related with the classical cGAS/STING pathway. NR2F6 binds to the promoter of MAP3K5 and activate AP-1/c-Jun pathway, which is critical for DNA virus replication. On the contrary, NR2F6 expression is transcriptionally repressed by c-Jun upon HSV-1 infection, which forms a negative feedback loop. Meanwhile, cGAS/STING innate immunity signaling represses NR2F6 through STAT3. Taken together, we have identified new transcription factors involved in the interactive network between DNA viruses and host cells, and revealed the underlying mechanisms for anti-viral research.