학술논문
The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression.
Document Type
Article
Author
Mas, Gloria; Man, Na; Yuichiro Nakata; Martinez-Caja, Concepcion; Karl, Daniel; Beckedorff, Felipe; Tamiro, Francesco; Chuan Chen; Duffort, Stephanie; Hidehiro Itonaga; 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.
Source
Subject
*GENE expression
*HEMATOPOIETIC stem cells
*CHROMATIN-remodeling complexes
*BLOOD coagulation factor XIII
*MYELOID differentiation factor 88
*LEUCOPENIA
*NEUROLOGICAL disorders
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Language
ISSN
0021-9738
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 Dpf2eΔ/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. [ABSTRACT FROM AUTHOR]