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Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling

ABSTRACT: Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling

PROVIDER: PRJNA603763 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10985237_1.fastq.gz	Fastqsanger.gz
	SRR10985237_2.fastq.gz	Fastqsanger.gz
	SRR10985238_1.fastq.gz	Fastqsanger.gz
	SRR10985238_2.fastq.gz	Fastqsanger.gz
	SRR10985239_1.fastq.gz	Fastqsanger.gz

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Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling: HP scRNA-seq

Project description:RUNX1 is frequently mutated in myeloid and lymphoid malignancies. It has been shown to negatively regulate Toll-like receptor 4 (TLR4) signaling through nuclear factor kappa-B (NF-κB) in lung epithelial cells. Here we show that RUNX1 regulates TLR1/2 and TLR4 signaling and inflammatory cytokine production by neutrophils. Hematopoietic-specific RUNX1 loss increased the production of pro-inflammatory mediators, including tumor necrosis factor α (TNF-α), by bone marrow (BM) neutrophils in response to TLR1/2 and TLR4 agonists. Hematopoietic RUNX1 loss also resulted in profound damage to the lung parenchyma following inhalation of the TLR4 ligand lipopolysaccharide (LPS). However, neutrophils with neutrophil-specific RUNX1 loss lacked the inflammatory phenotype caused by pan-hematopoietic RUNX1 loss, indicating that dysregulated TLR4 signaling is not due to loss of RUNX1 in neutrophils per se, and single cell RNA sequencing indicates the dysregulation originates in a neutrophil precursor. Enhanced inflammatory cytokine production by neutrophils following pan-hematopoietic RUNX1 loss correlated with increased degradation of the inhibitor of NF-κB signaling (IκBα), and RUNX1-deficient neutrophils displayed broad transcriptional upregulation of many of the core components of the TLR4 signaling pathway. Hence early, pan-hematopoietic RUNX1 loss de-represses an innate immune signaling transcriptional program that is maintained in terminally differentiated neutrophils, resulting in their hyper-inflammatory state. We hypothesize that inflammatory cytokine production by neutrophils may contribute to leukemia associated with inherited RUNX1 mutations.

2020-02-17 | GSE144482 | GEO

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling: PMN bulk RNA-seq

2020-02-17 | GSE144481 | GEO

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling: HP scRNA-seq

Project description:Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling: HP scRNA-seq

| PRJNA603768 | ENA

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling: PMN bulk RNA-seq

Project description:Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling: PMN bulk RNA-seq

| PRJNA603770 | ENA

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling.

Project description:RUNX1 is frequently mutated in myeloid and lymphoid malignancies. It has been shown to negatively regulate Toll-like receptor 4 (TLR4) signaling through nuclear factor κB (NF-κB) in lung epithelial cells. Here we show that RUNX1 regulates TLR1/2 and TLR4 signaling and inflammatory cytokine production by neutrophils. Hematopoietic-specific RUNX1 loss increased the production of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), by bone marrow neutrophils in response to TLR1/2 and TLR4 agonists. Hematopoietic RUNX1 loss also resulted in profound damage to the lung parenchyma following inhalation of the TLR4 ligand lipopolysaccharide (LPS). However, neutrophils with neutrophil-specific RUNX1 loss lacked the inflammatory phenotype caused by pan-hematopoietic RUNX1 loss, indicating that dysregulated TLR4 signaling is not due to loss of RUNX1 in neutrophils per se. Rather, single-cell RNA sequencing indicates the dysregulation originates in a neutrophil precursor. Enhanced inflammatory cytokine production by neutrophils following pan-hematopoietic RUNX1 loss correlated with increased degradation of the inhibitor of NF-κB signaling, and RUNX1-deficient neutrophils displayed broad transcriptional upregulation of many of the core components of the TLR4 signaling pathway. Hence, early, pan-hematopoietic RUNX1 loss de-represses an innate immune signaling transcriptional program that is maintained in terminally differentiated neutrophils, resulting in their hyperinflammatory state. We hypothesize that inflammatory cytokine production by neutrophils may contribute to leukemia associated with inherited RUNX1 mutations.

| S-EPMC7094023 | biostudies-literature

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-02-17 | GSE144483 | GEO

Epigenetic and transcriptomic alterations in key inflammatory pathways are established in RUNX1 deficient hematopoietic progenitors and are propagated to neutrophils [RNA-seq]

Project description:Epigenome and transcriptome characterization of RUNX1 deficient hematopoietic cells. We hypothesized that epigenetic alterations in key inflammatory pathway genes are acquired in RUNX1 deficient granulocyte-monocyte progenitors (GMPs) and are propagated to neutrophils. We deleted RUNX1 using Cebpa-Cre, which deletes primarily in GMPs. We analyzed the basal transcriptional changes caused by the loss of RUNX1 in purified GMPs and neutrophils by bulk RNA-seq. We evaluated if the loss of RUNX1 leads to changes in chromatin accessibility in GMPs and neutrophils by ATAC-seq. We determined that there was increased chromatin accessibility of transposable elements (TEs) in RUNX1 deficient cells. To determine if we could detect dsRNA from TEs, we pulled down dsRNA using the 9D5 antibody and performed RNA-seq. To gain insight into how RUNX1 loss affects active enhancers, we performed H3K27ac ChIP-seq on control and Runx1 deficient neutrophils. We also evaluated if RUNX1 mutations in patient neutrophils lead to changes in chromatin accessibility by ATAC-seq. We then performed Hi-C to evaluate the global high-order chromatin organization in GMPs and neutrophils. Finally, we performed RUNX1 CUT&RUN to determine RUNX1 occupancy sites in GMPs.

2023-07-12 | GSE221425 | GEO