The SWI/SNF chromatin remodeling subunit DPF2 facilitates NRF2-dependent anti-inflammatory and anti-oxidant gene expression
In: Journal of Clinical Investigation, vol 133, iss 13, 2023
academicJournal
Zugriff:
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.
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The SWI/SNF chromatin remodeling subunit DPF2 facilitates NRF2-dependent anti-inflammatory and anti-oxidant gene expression
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Autor/in / Beteiligte Person: | Mas, Gloria ; Man, Na ; Nakata, Yuichiro ; Martinez-Caja, Concepcion ; Karl, Daniel L ; 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 ; Morey, Lluis ; Bilbao, Daniel ; Nimer, Stephen D |
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Zeitschrift: | Journal of Clinical Investigation, vol 133, iss 13, 2023 |
Veröffentlichung: | eScholarship, University of California, 2023 |
Medientyp: | academicJournal |
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