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

Author:

Ahmed Nasiha S.1ORCID,Gatchalian Jovylyn1ORCID,Ho Josephine1,Burns Mannix J.1ORCID,Hah Nasun2,Wei Zong3ORCID,Downes Michael4ORCID,Evans Ronald M.4ORCID,Hargreaves Diana C.1ORCID

Affiliation:

1. Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;

2. Chapman Foundations Genomic Sequencing Core, Salk Institute for Biological Studies, La Jolla, CA 92037;

3. Department of Physiology and Biomedical Engineering, Mayo Clinic Arizona, Scottsdale, AZ 85249;

4. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037

Abstract

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.

Funder

HHS | NIH | National Institute of General Medical Sciences

HHS | NIH | National Cancer Institute

HHS | NIH | National Institute of Allergy and Infectious Diseases

Pew Charitable Trusts

American Cancer Society

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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