期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：1
DOI：10.1073/pnas.2110812119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Macrophages regulate many aspects of the innate immune response and the activation of adaptive immunity following exposure to microbial ligands. However, macrophages can also contribute to inflammation underlying diseases such as atherosclerosis and obesity. Epigenetic regulators control inflammatory gene regulation and, as such, are potential targets for modulation of the inflammatory response. Here, we show that inhibitors and degraders of the bromodomain protein BRD9, a subunit of the noncanonical BAF complex, limit inflammation by specifically blocking the induction of interferon-stimulated genes. This effect overlaps with the transcriptional responses with the BET inhibitor JQ1 but affects fewer genes and is more specific in scope. Our results suggest that BRD9 inhibitors/degraders may be therapeutically relevant agents to limit interferon-associated inflammation.
Macrophages induce a number of inflammatory response genes in response to stimulation with microbial ligands. In response to endotoxin Lipid A, a gene-activation cascade of primary followed by secondary-response genes is induced. Epigenetic state is an important regulator of the kinetics, specificity, and mechanism of gene activation of these two classes. In particular, SWI/SNF chromatin-remodeling complexes are required for the induction of secondary-response genes, but not primary-response genes, which generally exhibit open chromatin. Here, we show that a recently discovered variant of the SWI/SNF complex, the noncanonical BAF complex (ncBAF), regulates secondary-response genes in the interferon (IFN) response pathway. Inhibition of bromodomain-containing protein 9 (BRD9), a subunit of the ncBAF complex, with BRD9 bromodomain inhibitors (BRD9i) or a degrader (dBRD9) led to reduction in a number of interferon-stimulated genes (ISGs) following stimulation with endotoxin lipid A. BRD9-dependent genes overlapped highly with a subset of genes differentially regulated by BET protein inhibition with JQ1 following endotoxin stimulation. We find that the BET protein BRD4 is cobound with BRD9 in unstimulated macrophages and corecruited upon stimulation to ISG promoters along with STAT1, STAT2, and IRF9, components of the ISGF3 complex activated downstream of IFN-alpha receptor stimulation. In the presence of BRD9i or dBRD9, STAT1-, STAT2-, and IRF9-binding is reduced, in some cases with reduced binding of BRD4. These results demonstrate a specific role for BRD9 and the ncBAF complex in ISG activation and identify an activity for BRD9 inhibitors and degraders in dampening endotoxin- and IFN-dependent gene expression.
关键词：eninflammationmacrophagesBRD9bromodomain protein 9BRD4
