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The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression

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 a...

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Autores principales: Mas, Gloria, Man, Na, Nakata, Yuichiro, Martinez-Caja, Concepcion, Karl, Daniel, 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313367/
https://www.ncbi.nlm.nih.gov/pubmed/37200093
http://dx.doi.org/10.1172/JCI158419
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author Mas, Gloria
Man, Na
Nakata, Yuichiro
Martinez-Caja, Concepcion
Karl, Daniel
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.
author_facet Mas, Gloria
Man, Na
Nakata, Yuichiro
Martinez-Caja, Concepcion
Karl, Daniel
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.
author_sort Mas, Gloria
collection PubMed
description 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 Dpf2(Δ/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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spelling pubmed-103133672023-07-03 The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression Mas, Gloria Man, Na Nakata, Yuichiro Martinez-Caja, Concepcion Karl, Daniel 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. J Clin Invest Research Article 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 Dpf2(Δ/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. American Society for Clinical Investigation 2023-07-03 /pmc/articles/PMC10313367/ /pubmed/37200093 http://dx.doi.org/10.1172/JCI158419 Text en © 2023 Mas et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Mas, Gloria
Man, Na
Nakata, Yuichiro
Martinez-Caja, Concepcion
Karl, Daniel
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.
The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression
title The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression
title_full The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression
title_fullStr The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression
title_full_unstemmed The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression
title_short The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression
title_sort swi/snf chromatin-remodeling subunit dpf2 facilitates nrf2-dependent antiinflammatory and antioxidant gene expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313367/
https://www.ncbi.nlm.nih.gov/pubmed/37200093
http://dx.doi.org/10.1172/JCI158419
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