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The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene
Gloria Mas1, Na Man1, Yuichiro Nakata1,2
1Sylvester Comprehensive Cancer Center and.
The Journal of Clinical Investigation
|May 18, 2023
Summary
Double PHD fingers 2 (DPF2) is crucial for preventing lethal inflammation by regulating hematopoietic stem cells (HSCs) and immune cells. Restoring NRF2 function resolves DPF2-deficiency-induced hyperinflammation.
Area of Science:
- Immunology
- Hematology
- Molecular Biology
Background:
- Emergency hematopoiesis is vital for infection response but can cause chronic inflammation and disease if unresolved.
- Sustained inflammation is linked to life-threatening conditions and cancer.
- Double PHD fingers 2 (DPF2), a subunit of the BAF chromatin-remodeling complex, is implicated in cancer and neurological disorders.
Purpose of the Study:
- To investigate the role of DPF2 in modulating inflammation during emergency hematopoiesis.
- To understand the molecular mechanisms by which DPF2 controls inflammatory responses.
- To explore therapeutic strategies targeting DPF2-mediated pathways.
Main Methods:
- Generation and analysis of hematopoiesis-specific Dpf2-knockout (Dpf2-KO) mice.
- Assessment of hematopoietic stem cell (HSC) function, immune cell populations, and inflammatory markers.
- Chromatin immunoprecipitation sequencing (ChIP-seq) to identify DPF2-associated genomic regions.
- Pharmacological intervention using NRF2 activators.
Main Results:
- Dpf2-KO mice exhibited leukopenia, anemia, and lethal systemic inflammation with tissue infiltration.
- Dpf2 loss led to impaired macrophage polarization, unrestrained T helper (Th) cell activation, and HSC hyperproliferation.
- DPF2 deficiency caused loss of BRG1 from NRF2-controlled enhancers, hindering antioxidant and anti-inflammatory responses.
- Pharmacological reactivation of NRF2 ameliorated inflammation and rescued Dpf2Δ/Δ mice from lethality.
Conclusions:
- The DPF2-BAF complex is essential for licensing NRF2-dependent gene expression in HSCs and immune cells.
- DPF2 plays a critical role in preventing chronic inflammation by maintaining immune homeostasis.
- Targeting the DPF2-BAF-NRF2 axis offers a potential therapeutic strategy for inflammatory diseases.
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