Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils

Fischer, Josephine; Walter, Carolin; Tönges, Alexander; Aleth, Hanna; Jordão, Marta Joana Costa; Leddin, Mathias; Gröning, Verena; Erdmann, Tabea; Lenz, Georg; Röth, Jürgen; Vogl, Thomas J.; Prinz, Marco; Dugas, Martin; Jacobsen, Ilse D.; Rosenbauer, Frank

doi:10.1038/s41590-019-0343-z

Cited by 41 publications

(39 citation statements)

References 70 publications

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“…Several types of immune cells express JunB and other Jun family proteins, and upon cell stimulation, phosphorylation of JunB by the upstream MAPK JNKs has been shown to greatly increase the ability of JunB to induce the transactivation . Neutrophils constitutively express a number of the Jun family proteins and among them, JunB has been found to be mostly expressed and accessible upon neutrophil activation . Recent evidence suggests that JunB strongly enhances immune gene expression by binding to the promoter‐proximal regions upstream to the genes that control infection and inflammation whereas PU.1 , a myeloid transcriptional regulator, inhibits JunB access to the chromatin by recruiting histone deacetylase (HDAC) to the JunB binding enhancers, consequently attenuating neutrophil activity, suggesting that JunB is of importance in positively regulating neutrophil functions.…”

Section: Neutrophil Activationmentioning

confidence: 99%

“…Neutrophils constitutively express a number of the Jun family proteins and among them, JunB has been found to be mostly expressed and accessible upon neutrophil activation . Recent evidence suggests that JunB strongly enhances immune gene expression by binding to the promoter‐proximal regions upstream to the genes that control infection and inflammation whereas PU.1 , a myeloid transcriptional regulator, inhibits JunB access to the chromatin by recruiting histone deacetylase (HDAC) to the JunB binding enhancers, consequently attenuating neutrophil activity, suggesting that JunB is of importance in positively regulating neutrophil functions. More studies are required to reveal the functional role of JunB activation in neutrophils.…”

Section: Neutrophil Activationmentioning

confidence: 99%

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Transcriptional regulation of neutrophil differentiation and function during inflammation

Udalova

2020

Journal of Leukocyte Biology

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Neutrophils are the most abundant leukocytes in innate immunity where they elicit powerful effector functions to eliminate invading pathogens and modulate the adaptive as well as the innate immune response. Neutrophil function must be tightly regulated during inflammation and infection to avoid additional tissue damage. Increasing evidence suggests that transcription factors (TFs) function as key regulators to modulate transcriptional output, thereby controlling cell fate decision and the inflammatory responses. However, the molecular mechanisms underlying neutrophil differentiation and function during inflammation remain largely uncharacterized. Here, we provide a comprehensive overview of TFs known to be crucial for neutrophil maturation and in the signaling pathways that control neutrophil differentiation and activation. We also outline how emerging genomic and single‐cell technologies may facilitate further discovery of neutrophil transcriptional regulators.

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Section: Neutrophil Activationmentioning

confidence: 99%

Section: Neutrophil Activationmentioning

confidence: 99%

Transcriptional regulation of neutrophil differentiation and function during inflammation

Udalova

2020

Journal of Leukocyte Biology

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“…As a pioneer TF, PU.1 is able to bind these regions in a repressive chromatin state and activate them via the recruitment of other factors 21 , including core chromatin activators and TFs such as C/EBPβ, which is expressed throughout neutrophil development 22 . PU.1 is required for modulating the response of mouse neutrophils to infection 23 , but the emerging evidence for a role of this factor in complex diseases is currently limited to other cell types. For example, a common genetic variant within the SPI1 gene was found to be associated with Alzheimer's disease, with microglial cells proposed as the likely causal cell type 24 .…”

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confidence: 99%

Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease

et al. 2021

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Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.

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“…We have previously reported that Aβ-induced damage was closely related to proinflammatory cytokine production, and ChIP-seq analysis showed that PU.1 regulated the expression of genes relevant to Aβ-activated microglia 64 . Therefore, further investigation is required to elucidate whether PU.1 is related to RPE cell inflammation and whether epigenetic modification via histone deacetylase 1 occurs in addition to transcriptional regulation, as reported in a previous study 65 .…”

Section: Discussionmentioning

confidence: 93%

ROS production and mitochondrial dysfunction driven by PU.1-regulated NOX4-p22^phox activation in Aβ-induced retinal pigment epithelial cell injury

Sun¹,

Chen²,

Li³

et al. 2020

Theranostics

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Rationale: Amyloid β (Aβ) deposition, an essential pathological process in age-related macular degeneration (AMD), causes retinal pigment epithelium (RPE) degeneration driven mostly by oxidative stress. However, despite intense investigations, the extent to which overoxidation contributes to Aβ-mediated RPE damage and its potential mechanism has not been fully elucidated. Methods: We performed tandem mass-tagged (TMT) mass spectrometry (MS) and bioinformatic analysis of the RPE-choroid complex in an Aβ 1-40 -induced mouse model of retinal degeneration to obtain a comprehensive proteomic profile. Key regulators in this model were confirmed by reactive oxygen species (ROS) detection, mitochondrial ROS assay, oxygen consumption rate (OCR) measurement, gene knockout experiment, chromatin immunoprecipitation (ChIP), and luciferase assay. Results: A total of 4243 proteins were identified, 1069 of which were significantly affected by Aβ 1-40 and found to be enriched in oxidation-related pathways by bioinformatic analysis. Moreover, NADPH oxidases were identified as hub proteins in Aβ 1-40 -mediated oxidative stress, as evidenced by mitochondrial dysfunction and reactive oxygen species overproduction. By motif and binding site analyses, we found that the transcription factor PU.1/Spi1 acted as a master regulator of the activation of NADPH oxidases, especially the NOX4-p22 phox complex. Also, PU.1 silencing impeded RPE oxidative stress and mitochondrial dysfunction and rescued the retinal structure and function. Conclusion: Our study suggests that PU.1 is a novel therapeutic target for AMD, and the regulation of PU.1 expression represents a potentially novel approach against excessive oxidative stress in Aβ-driven RPE injury.

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Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils

Cited by 41 publications

References 70 publications

Transcriptional regulation of neutrophil differentiation and function during inflammation

Transcriptional regulation of neutrophil differentiation and function during inflammation

Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease

ROS production and mitochondrial dysfunction driven by PU.1-regulated NOX4-p22^phox activation in Aβ-induced retinal pigment epithelial cell injury

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Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils

Cited by 41 publications

References 70 publications

Transcriptional regulation of neutrophil differentiation and function during inflammation

Transcriptional regulation of neutrophil differentiation and function during inflammation

Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease

ROS production and mitochondrial dysfunction driven by PU.1-regulated NOX4-p22phox activation in Aβ-induced retinal pigment epithelial cell injury

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ROS production and mitochondrial dysfunction driven by PU.1-regulated NOX4-p22^phox activation in Aβ-induced retinal pigment epithelial cell injury