The Swi/Snf Chromatin-Remodeling Subunit DPF2 Facilitates NRF2-Dependent Antiinflammatory and Antioxidant Gene Expression

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

Publication Date

7-3-2023

Journal

The Journal of Clinical Investigation

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.

Keywords

Mice, Animals, Chromatin, Antioxidants, NF-E2-Related Factor 2, Neoplasms, Chromatin Assembly and Disassembly, Inflammation, Gene Expression, DNA-Binding Proteins, Transcription Factors, Epigenetics, Hematopoietic stem cells, Macrophages

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Associated Data

PMID: 37200093