期刊
EMBO REPORTS
卷 22, 期 10, 页码 -出版社
WILEY
DOI: 10.15252/embr.202152823
关键词
bromodomain; chromatin; epigenetics; interferon; virus
资金
- Functional Genomics Center Zurich
- Cytometry Facility, University of Zurich
- Swiss National Science Foundation [31003A_182464]
- Swiss National Science Foundation (SNF) [31003A_182464] Funding Source: Swiss National Science Foundation (SNF)
The study identified BRD9 as a critical factor for IFN-induced ISG expression, and genetic knockout or degradation of BRD9 can limit ISG expression and attenuate the antiviral activity of IFN. BRD9 acts at the transcriptional level through interactions with factors like STAT2, possibly serving as an important regulatory factor for inhibiting ISG expression.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据