Alternate isoforms of IRF7 Differentially Regulate Interferon Expression

Interferon Regulatory Factor 7 (IRF7), and its homologue IRF3, are master transcriptional regulators of the innate immune response. IRF7 binds to promoters of interferon beta (IFNb) and several IFNas, as a homodimer or as a heterodimer with IRF3 to drive expression of these type I IFNs, which in turn activate additional signaling pathways to promote expression of anti-viral genes. Here we demonstrate that retention of the first intron within the coding region of IRF7 is highly regulated across immune tissues and in response to viral infection and other immunologic signals. Importantly, retention of this intron generates an alternative translation start site, resulting in a N-terminally extended form of the protein (exIRF7). Using CRISPR gene editing to generate cells that only express exIRF7, or the canonical version of IRF7 (cIRF7), we demonstrate that exIRF7 uniquely activates a program of genes, including IFNb, in response to innate immune triggers. We conclude that alternative splicing of IRF7 is a previously unrecognized mechanisms used by human cells to tune the interferon response to viral infection and other immune challenges. Overall design: RNA-seq profiling of Jurkat T-cells (JSL1) engineered by CRISPR to be deficient in IRF7 or express solely one spliced isoform. Cells were untreated or treated with either IFNa or poly(I:C) for 8 hours