The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression

• Published in: The Journal of clinical investigation Vol. 133; no. 13; pp. 1 - 18
• Main Authors: Mas, Gloria, Man, Na, Nakata, Yuichiro, Martinez-Caja, Concepcion, Karl, Daniel, Beckedorff, Felipe, Tamiro, Francesco, Chen, Chuan, Duffort, Stephanie, Itonaga, Hidehiro, Mookhtiar, Adnan K, Kunkalla, Kranthi, Valencia, Alfredo M, Collings, Clayton K, Kadoch, Cigall, Vega, Francisco, Kogan, Scott C, Shiekhattar, Ramin, Morey, Lluis, Bilbao, Daniel, Nimer, Stephen D
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 03.07.2023
• Subjects: Anemia; Animals; Antioxidants; Biomedical research; BRG1 protein; Cancer; Cell activation; Cell differentiation; Chromatin; Chromatin Assembly and Disassembly; Chromatin remodeling; Cytokines; Development and progression; DNA-Binding Proteins - genetics; Effector cells; Enhancers; Gene Expression; Genetic aspects; Health aspects; Helper cells; Hematology; Hematopoietic stem cells; Hemopoiesis; Inflammation; Inflammation - genetics; Lethality; Leukopenia; Liver; Lungs; Lymphocytes T; Macrophages; Mice; Neoplasms; Neurological diseases; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NRF2 protein; Phenotypes; Physiological aspects; Stem cells; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; United States; Epigenetics; Inflammation; Hematology; Macrophages; Hematopoietic stem cells
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI158419

During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a clinical hyperinflammatory state. Dpf2 loss impaired the polarization of macrophages responsible for tissue repair, induced the unrestrained activation of Th cells, and generated an emergency-like state of HSC hyperproliferation and myeloid cell-biased differentiation. Mechanistically, Dpf2 deficiency resulted in the loss of the BAF catalytic subunit BRG1 from nuclear factor erythroid 2-like 2-controlled (NRF2-controlled) enhancers, impairing the antioxidant and antiinflammatory transcriptional response needed to modulate inflammation. Finally, pharmacological reactivation of NRF2 suppressed the inflammation-mediated phenotypes and lethality of Dpf2Δ/Δ mice. Our work establishes an essential role of the DPF2-BAF complex in licensing NRF2-dependent gene expression in HSCs and immune effector cells to prevent chronic inflammation.