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, Ramin Shiekhattar, Lluis Morey, Daniel Bilbao, Stephen D. Nimer

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Figure 4

BM of Dpf2Δ/Δ mice displays early expansion of macrophages and T cells, with impaired B cell and erythroid cell differentiation.

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BM of Dpf2Δ/Δ mice displays early expansion of macrophages and T cells, ...
(A) PB CBC from 14-day-old mice (n = 4). MCV, mean corpuscular volume. (B) Representative images of spleens from 14-day-old mice. (C) H&E staining of BM, liver, and lungs from 14-day old mice. Scale bars: 50 μm. (D) Plasma cytokine levels in 14-day-old mice. Values correspond to the mean spot pixel density relative to background in 4 mice/genotype. (E) Representative FACS plots of BM B cells and quantification of B cell frequency in BM, PB, and spleen of end-stage Dpf2Δ/Δ mice and Dpf2fl/fl littermates. (F) Representative FACS plots of BM erythroid cell maturation based on the expression of CD71 and Ter119 surface markers (107). FACS profiles resolve 5 distinct clusters: clusters IV and V (low CD44 and smaller size) correspond to orthochromatic erythroblasts, reticulocytes, and mature RBCs; clusters I, II, and III (higher CD44 and larger size) correspond to immature nucleated erythroblasts, specifically pro-erythroblasts, basophilic erythroblasts, and polychromatic erythroblasts, respectively. FSC-A, forward scatter area. Bar graph data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by 2-tailed, unpaired Student’s t test.