BRD9 is a druggable component of interferon‐stimulated gene expression and antiviral activity. (16th August 2021)

• Record Type: Journal Article
• Authors: Börold, Jacob; Eletto, Davide; Busnadiego, Idoia; Mair, Nina K; Moritz, Eva; Schiefer, Samira; Schmidt, Nora; Petric, Philipp P; Wong, W Wei‐Lynn; Schwemmle, Martin; Hale, Benjamin G
• Is Part Of: EMBO reports. Volume 22:Number 10(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-08-16
• Subjects: bromodomain -- chromatin -- epigenetics -- interferon -- virus; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202152823
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: Interferon signaling induces a potent antiviral state in cells. This study uses genome‐scale CRISPR/Cas9 screening as a basis to identify and characterize a new role for BRD9 in cellular interferon‐stimulated gene expression and antiviral activity. The non‐canonical chromatin remodeling complex component BRD9 is required for interferon‐stimulated gene expression. BRD9 function relies on its acetyl‐binding bromodomain and unique DUF3512 scaffolding domain. Depletion of BRD9 limits the antiviral action of interferon against several RNA and DNA viruses. Small molecule degraders of BRD9 may permit dampening of pathogenic autoinflammatory gene expression. Abstract : Interferon signaling induces a potent antiviral state in cells. This study uses genome‐scale CRISPR/Cas9 screening as a basis to identify and characterize a new role for BRD9 in cellular interferon‐stimulated gene expression and antiviral activity.