TY - JOUR
T1 - The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression
AU - Mas, Gloria
AU - Man, Na
AU - Nakata, Yuichiro
AU - Martinez-Caja, Concepcion
AU - Karl, Daniel
AU - Beckedorff, Felipe
AU - Tamiro, Francesco
AU - Chen, Chuan
AU - Duffort, Stephanie
AU - Itonaga, Hidehiro
AU - Mookhtiar, Adnan K.
AU - Kunkalla, Kranthi
AU - Valencia, Alfredo M.
AU - Collings, Clayton K.
AU - Kadoch, Cigall
AU - Vega, Francisco
AU - Kogan, Scott C.
AU - Morey, Lluis
AU - Bilbao, Daniel
AU - Nimer, Stephen D.
N1 - Publisher Copyright:
© 2023, Mas et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2023/7/3
Y1 - 2023/7/3
N2 - 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.
AB - 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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U2 - 10.1172/JCI158419
DO - 10.1172/JCI158419
M3 - Article
C2 - 37200093
AN - SCOPUS:85164211102
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 13
M1 - e158419
ER -