The SWI/SNF chromatin remodeling subunit DPF2 facilitates NRF2-dependent anti-inflammatory and anti-oxidant gene expression

Gloria Mas; Na Man; Yuichiro Nakata; Concepcion Martinez-Caja; Daniel L. 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; Lluis Morey; Daniel Bilbao; Stephen D. Nimer

doi:10.1172/JCI158419

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

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¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Mookhtiar, A. in: JCI | PubMed | Google Scholar

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Kunkalla, K. in: JCI | PubMed | Google Scholar

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Valencia, A. in: JCI | PubMed | Google Scholar |

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Collings, C. in: JCI | PubMed | Google Scholar |

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Kadoch, C. in: JCI | PubMed | Google Scholar

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Vega, F. in: JCI | PubMed | Google Scholar |

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Kogan, S. in: JCI | PubMed | Google Scholar |

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Morey, L. in: JCI | PubMed | Google Scholar |

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Bilbao, D. in: JCI | PubMed | Google Scholar

¹Sylvester Comprehensive Cancer Center, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

²Department of Human Genetics, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States of America

³Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁴Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States of America

⁵Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, United States of America

⁶Comprehensive Cancer Center, University of California San Francisco, San Francisco, United States of America

Find articles by Nimer, S. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI158419.
Copyright © 2023, Mas et al. 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/.

Published May 18, 2023 - Version history

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. We have identified a novel role of Dpf2 in inflammation. Dpf2 is a defining subunit of the hematopoietic-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncover that hematopoietic-specific Dpf2 knock-out mice develop leukopenia, severe anemia and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration, resembling a clinical hyper-inflammatory state. Dpf2 loss impairs the polarization of macrophages responsible for tissue repair, induces unrestrained activation of T helper cells, and generates an emergency-like state of HSC hyperproliferation and myeloid-biased differentiation. Mechanistically, Dpf2 deficiency results in the loss of the BAF catalytic subunit Brg1 from Nrf2-controlled enhancers, impairing the anti-oxidant and anti-inflammatory transcriptional response needed to modulate inflammation. Finally, pharmacological reactivation of Nrf2 can suppress the inflammation-mediated phenotypes and lethality of Dpf2^Δ/Δ mice. Our work establishes the essential role of the Dpf2/BAF complex in licensing Nrf2-dependent gene expression in HSCs and immune effector cells to prevent chronic inflammation.

Version 1 (May 18, 2023): In-Press Preview

The SWI/SNF chromatin remodeling subunit DPF2 facilitates NRF2-dependent anti-inflammatory and anti-oxidant gene expression

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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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