The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression
Gloria Mas, … , Daniel Bilbao, Stephen D. Nimer
Gloria Mas, … , Daniel Bilbao, Stephen D. Nimer
Published May 18, 2023
Citation Information: J Clin Invest. 2023;133(13):e158419. https://doi.org/10.1172/JCI158419.
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Research Article Hematology Inflammation

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

Abstract

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.

Authors

Gloria Mas, Na Man, Yuichiro Nakata, Concepcion Martinez-Caja, Daniel Karl, Felipe Beckedorff, Francesco Tamiro, Chuan Chen, Stephanie Duffort, Hidehiro Itonaga, Adnan K. Mookhtiar, Kranthi Kunkalla, Alfredo M. Valencia, Clayton K. Collings, Cigall Kadoch, Francisco Vega, Scott C. Kogan, Lluis Morey, Daniel Bilbao, Stephen D. Nimer

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Figure 1

Hematopoiesis-specific, Vav1-Cre–mediated loss of Dpf2 leads to premature death from pancytopenia and inflammatory lesions.

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Hematopoiesis-specific, Vav1-Cre–mediated loss of Dpf2 leads to prematur...
(A) Representative images of Vav1-Cre–derived 28-day-old mice. (B) Total BWs of 28-day-old mice. (C) Kaplan-Meier survival curves; the median survival of Dpf2Δ/Δ mice was 28 days. (D) Representative images of organs from 28-day-old mice. (E) Total number of cells in BM, spleen, and thymus. (F) CBC of PB in approximately 28-day-old mice (n = 18). Hb, hemoglobin; PLT, platelets. (G) Representative H&E staining of BM, spleen, and thymus from 28-day-old mice. Scale bars: 50 μm. (H and I) Representative H&E staining of liver (G) and lung (H) from end-stage Dpf2Δ/Δ and age-matched Dpf2fl/fl mice. Scale bars: 200 μm. (J) Representative CD68/macrosialin IHC staining of lung and liver. Scale bars: 200 μm (lung IHC), 50 μm (Dpf2fl/fl liver), and 100 μm (Dpf2Δ/Δ liver). (K) Representative CD69 IHC staining of lung and liver infiltrates. Scale bars: 50 μm. (L) Plasma cytokine levels. Values correspond to the mean spot pixel density relative to background from 4 mice/genotype. (M) Chemistry profiling of PB from 28-day-old mice (n = 3). (N) Serum ferritin and sCD25 plasma levels. All bar graph data represent the mean ± SD. ***P < 0.001, by 2-tailed, unpaired Student’s t test (B, M, and N) and ordinary, 1-way ANOVA (E and F).