BRD9 regulates interferon-stimulated genes during macrophage activation via cooperation with BET protein BRD4

Nasiha S. Ahmed, Jovylyn Gatchalian, Josephine Ho, Mannix J. Burns, Nasun Hah, Zong Wei, Michael Downes, Ronald M. Evans, Diana C. Hargreaves

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere2110812119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number1
StatePublished - Jan 4 2022


  • BRD4
  • BRD9
  • Bromodomain protein 9
  • Inflammation
  • Macrophages

ASJC Scopus subject areas

  • General


Dive into the research topics of 'BRD9 regulates interferon-stimulated genes during macrophage activation via cooperation with BET protein BRD4'. Together they form a unique fingerprint.

Cite this