Abstract
Interferon (IFN) induction of IFN-stimulated genes (ISGs) creates a formidable protective antiviral state. However, loss of appropriate control mechanisms can result in constitutive pathogenic ISG upregulation. Here, we used genome-scale loss-of-function screening to establish genes critical for IFN-induced transcription, identifying all expected members of the JAK-STAT signaling pathway and a previously unappreciated epigenetic reader, bromodomain-containing protein 9 (BRD9), the defining subunit of non-canonical BAF (ncBAF) chromatin-remodeling complexes. Genetic knockout or small-molecule-mediated degradation of BRD9 limits IFN-induced expression of a subset of ISGs in multiple cell types and prevents IFN from exerting full antiviral activity against several RNA and DNA viruses, including influenza virus, human immunodeficiency virus (HIV1), and herpes simplex virus (HSV1). Mechanistically, BRD9 acts at the level of transcription, and its IFN-triggered proximal association with the ISG transcriptional activator, STAT2, suggests a functional localization at selected ISG promoters. Furthermore, BRD9 relies on its intact acetyl-binding bromodomain and unique ncBAF scaffolding interaction with GLTSCR1/1L to promote IFN action. Given its druggability, BRD9 is an attractive target for dampening ISG expression under certain autoinflammatory conditions.
Highlights
Interferon (IFN) induction of IFN-stimulated genes (ISGs) creates a formidable protective antiviral state
The type I IFN signaling pathway leading to induction of ISG expression is comprised of several canonical gene components, including receptors (IFNAR1, IFNAR2), kinases (JAK1, TYK2), and transcription factors (ISGF3: STAT1, STAT2, IFN-regulatory factor 9 (IRF9)) (Fig 1A)
Of the 333 IFNupregulated genes (ISGs) we identified in A549 cells, we found that prior dBRD9-A treatment led to significantly reduced induction of 29 ISGs, including many ISGs known to harbor antiviral activity against the viruses used in this study, such as MX1, MX2, IFITM1, IFITM3, IDO1, and BST2 (Fig 4C, Dataset EV2)
Summary
Interferon (IFN) induction of IFN-stimulated genes (ISGs) creates a formidable protective antiviral state. We used genome-scale lossof-function screening to establish genes critical for IFN-induced transcription, identifying all expected members of the JAK-STAT signaling pathway and a previously unappreciated epigenetic reader, bromodomain-containing protein 9 (BRD9), the defining subunit of non-canonical BAF (ncBAF) chromatin-remodeling complexes. Genetic knockout or small-molecule-mediated degradation of BRD9 limits IFN-induced expression of a subset of ISGs in multiple cell types and prevents IFN from exerting full antiviral activity against several RNA and DNA viruses, including influenza virus, human immunodeficiency virus (HIV1), and herpes simplex virus (HSV1). BRD9 acts at the level of transcription, and its IFN-triggered proximal association with the ISG transcriptional activator, STAT2, suggests a functional localization at selected ISG promoters. BRD9 is an attractive target for dampening ISG expression under certain autoinflammatory conditions
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