Serine/arginine-rich splicing factor 7 promotes the type I interferon response by activating Irf7 transcription

• Published in: Cell reports (Cambridge) 2024-03, Vol.43 (3), p.113816-113816, Article 113816
• Main Authors: Scott, Haley M., Smith, Mackenzie H., Coleman, Aja K., Armijo, Kaitlyn S., Chapman, Morgan J., Apostalo, Summer L., Wagner, Allison R., Watson, Robert O., Patrick, Kristin L.
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; antiviral immunity; chromatin; co-transcriptional splicing; CP: Cell biology; CP: Molecular biology; histone methylation; Humans; innate immunity; Interferon Type I; Macrophages; pre-mRNA splicing; Promoter Regions, Genetic - genetics; RNA binding proteins; RNA Splicing Factors; Serine-Arginine Splicing Factors - genetics; Transcription, Genetic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113816

Tight regulation of macrophage immune gene expression is required to fight infection without risking harmful inflammation. The contribution of RNA-binding proteins (RBPs) to shaping the macrophage response to pathogens remains poorly understood. Transcriptomic analysis reveals that a member of the serine/arginine-rich (SR) family of mRNA processing factors, SRSF7, is required for optimal expression of a cohort of interferon-stimulated genes in macrophages. Using genetic and biochemical assays, we discover that in addition to its canonical role in regulating alternative splicing, SRSF7 drives transcription of interferon regulatory transcription factor 7 (IRF7) to promote antiviral immunity. At the Irf7 promoter, SRSF7 maximizes STAT1 transcription factor binding and RNA polymerase II elongation via cooperation with the H4K20me1 histone methyltransferase KMT5a (SET8). These studies define a role for an SR protein in activating transcription and reveal an RBP-chromatin network that orchestrates macrophage antiviral gene expression. [Display omitted] •The splicing factor SRSF7 is needed for a robust antiviral response in macrophages•SRSF7 licenses expression of the antiviral transcription factor Irf7•SRSF7 promotes STAT1 binding and RNAPII elongation at the Irf7 promoter•With KMT5a, SRSF7 helps establish a pro-transcription chromatin landscape at Irf7 There is a growing appreciation for splicing factors activating transcription of genes. Here, Scott et al. implicate serine-arginine splicing factor 7 (SRSF7) in facilitating transcription of the antiviral transcription factor Irf7. By engaging with nascent Irf7 transcripts at the Irf7 genomic locus, SRSF7 promotes deposition of H4K20me1 by KMT5a and enables recruitment of STAT1 to the Irf7 promoter.