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Setd2 deficiency impaired erythroid differentiation and accelerated Myelodysplastic Syndrome(MDS) - associated leukemogenesis through S100A8 and S100A9

ABSTRACT: Setd2 deficiency impaired erythroid differentiation and accelerated Myelodysplastic Syndrome(MDS) - associated leukemogenesis through S100A8 and S100A9

PROVIDER: PRJNA532447 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8885380_1.fastq.gz	Fastqsanger.gz
	SRR8885380_2.fastq.gz	Fastqsanger.gz
	SRR8885390_1.fastq.gz	Fastqsanger.gz
	SRR8885390_2.fastq.gz	Fastqsanger.gz
	SRR8885381_1.fastq.gz	Fastqsanger.gz

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Setd2 deficiency impaired erythroid differentiation and accelerated Myelodysplastic Syndrome(MDS) - associated leukemogenesis through S100A8 and S100A9

Project description:Setd2, the histone H3 lysine 36 methyltransferase, plays an important role in the pathogenesis of hematologic malignancies. The research on the role of Setd2 in leukemogenesis has made great progress, but its role in MDS is still unknown. Here, we knock out Setd2 in the NUP98-HOXD13 transgenic (NHD13 Tg) mouse, and demonstrate that loss of Setd2 accelerates the transformation of MDS into AML. The conditional deletion of Setd2 also interferes the differentiation of hematopoietic stem and progenitor cells (HSPCs), and results in the decrease of granulocyte monocyte progenitor (GMP) cells, increase of megakaryocyte erythroid progenitor (MEP) cells and common myeloid progenitor (CMP) cells. Loss of Setd2 impairs erythroid differentiation, includes cell cycle arrest in G2-M and enhances the selt-renewal ability of HSPCS. Our RNA-seq,ChIP-seq and WGBS analysis indicats that S100A8 and S100A9 are direct target genes of H3K36me3 and expression of heterodimeric S100 calcium-binding proteins S100A8 and S100A9 are downregulated in HSPCs when Setd2 deficiency. Addition of recombinant S100A8 or S100A9 weakens the clonogenic progenitors of Setd2 deficient HSPCs. Therefore, our results demonstrate that loss of Setd2 promotes the transformation of MDS into AML, which proves Setd2 as a tumor suppressor in MDS, and provides a potential therapeutic target for MDS associated leukemia.

2020-07-02 | GSE129691 | GEO

Biological effects of recombinant S100A8, recombinant S100A9, and recombinant S100A8/S100A9 on human renal tubular epithelial cells (HK-2)

Project description:In order to explore how S100A8 and S100A9 may participate in the kidney stone formation, we used recombinant S100A8, recombinant S100A9, or recombinant S100A8/S100A9 heterodimer to culture the HK-2 cells and then sequenced total cellular mRNAS.

2024-11-06 | GSE265848 | GEO

S100A8/S100A9 cytokine functions as transcriptional coactivator during breast cellular transformation

Project description:In an inducible model of human breast cellular transformation, we map genome-wide chromatin binding of S100A8, S100A9 and Pol II. We show that the calcium-dependent cytokines S100A8 and S100A9 are recruited to numerous promoters and enhancers. This recruitment is associated with multiple DNA sequence motifs recognized by DNA-binding transcription factors that are linked to transcriptional activation and are important for transformation. Nuclear-specific expression of S100A8/A9 promotes oncogenic transcription and leads to enhanced breast transformation phenotype. These results suggest that, in addition to its classical cytokine function, S100A8/A9 can act as a transcriptional co-activator.

2021-01-01 | GSE155421 | GEO

Local restriction of sterile inflammation by auto-inhibitory regulation of S100A8/S100A9-alarmin activity

Project description:Autoimmune diseases, like psoriasis or arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals like Danger-Associated Molecular Pattern molecules (DAMPs) are indispensable for manifestation of local inflammation. S100A8/100A9-complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP-activities are barely understood. We now unravel for the first time a novel mechanism of auto-inhibition in mice and man restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry and targeted mutations we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9-heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9-activities are locally restricted by calcium-induced (S100A8/S100A9)2-tetramer formation now hiding the TLR4/MD2-binding site within the tetramer interphase thus preventing undesirable systemic effects. Loss of this auto-inhibitory mechanism in vivo results in TNFa-driven fatal inflammation as shown by lack of tetramer formation crossing S100A9-/- mice with two independent TNFa-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking of the TLR4-binding site of active S100-dimers represents an innovative approach for local suppression of inflammatory diseases avoiding systemic side effects.

2019-04-08 | GSE109426 | GEO

SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS.

Project description:SETD2, the histone H3 lysine 36 methyltransferase, previously identified by us, plays an important role in the pathogenesis of hematologic malignancies, but its role in myelodysplastic syndromes (MDSs) has been unclear. In this study, low expression of SETD2 correlated with shortened survival in patients with MDS, and the SETD2 levels in CD34+ bone marrow cells of those patients were increased by decitabine. We knocked out Setd2 in NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and found that loss of Setd2 accelerated the transformation of MDS into acute myeloid leukemia (AML). Loss of Setd2 enhanced the ability of NHD13+ hematopoietic stem and progenitor cells (HSPCs) to self-renew, with increased symmetric self-renewal division and decreased differentiation and cell death. The growth of MDS-associated leukemia cells was inhibited though increasing the H3K36me3 level by using epigenetic modifying drugs. Furthermore, Setd2 deficiency upregulated hematopoietic stem cell signaling and downregulated myeloid differentiation pathways in the NHD13+ HSPCs. Our RNA-seq and chromatin immunoprecipitation-seq analysis indicated that S100a9, the S100 calcium-binding protein, is a target gene of Setd2 and that the addition of recombinant S100a9 weakens the effect of Setd2 deficiency in the NHD13+ HSPCs. In contrast, downregulation of S100a9 leads to decreases of its downstream targets, including Ikba and Jnk, which influence the self-renewal and differentiation of HSPCs. Therefore, our results demonstrated that SETD2 deficiency predicts poor prognosis in MDS and promotes the transformation of MDS into AML, which provides a potential therapeutic target for MDS-associated acute leukemia.

| S-EPMC7316210 | biostudies-literature

Expression data for murine colon carcinoma cell line CT26.WT stimulated with S100a8 or S100a9 recombinant protein

Project description:Damage-associated molecular pattern (DAMP) molecules S100A8 and S100A9 with well-known functions in inflammation, tumor growth and metastasis. It has been found to have promote tumor cell proliferation activity at low concentration . However, the mechanism underlying this remains unclear. In the current study, we performed genome expression profiling analysis using the Affymetrix genome wide microarray system to identify broad scale changes in gene expression associated with S100a8 or S100a9 recombinant protein stimulation in murine colon carcinoma cell line CT26.WT.

2015-11-29 | GSE53735 | GEO

Biological effects of recombinant S100A8, recombinant S100A9, and recombinant S100A8/S100A9 on human renal tubular epithelial cells (HK-2)

Project description:Biological effects of recombinant S100A8, recombinant S100A9, and recombinant S100A8/S100A9 on human renal tubular epithelial cells (HK-2)

| PRJNA1104534 | ENA

S100A8 treatment on gene expression of human umbilical vascular endothelial cells.

Project description:Previous studies showed that S100A8 and S100A9 are involved in neovascularization as well as in tumor development. At high concentrations, S100A8 and S100A9 cause inflammatory response or apoptosis mediated damage in vascular endothelial cells. But the effect of low concentrations of such proteins on endothelial cells remains unknown. This assay was performed to screen for genes that are involved in the response of Human Unbilican Vascular Endothelial Cells to low concentrations of S100A8. Human Umblical Vascular Endothelial Cells (HUVEC) were cultuered and treated with 10ug/mL S100A8 proteins for 4 or 24 hours. Gene profiling was carried out using two-color microarray. Two-condition experiment, S100A8 treatment vs. non-treatment. Two time points: 4 hours and 24 hours. Biological replicates at each time point: 3 control replicates, 3 treatment replicates.

2011-11-20 | E-GEOD-33768 | biostudies-arrayexpress

A proteome-wide screen identifies the calcium binding proteins, S100A8/S100A9, as clinically relevant therapeutic targets in aortic dissection: a translational study [scRNA-seq]

Project description:S100A8 and S100A9 (aliases MRP8 and MRP14) are highly expressed in neutrophils and monocytes and are classified as damage-associated molecular pattern (DAMP) molecules or alarm molecules. However, the role of S100A8/A9 in aortic dissection has not been reported. In the present study, by employing an unbiased proteomics approach and RNA sequencing analysis , we found that the protein expression of calcium binding proteins S100A8/A9 were upregulated in the aorta and serum of TAAAD patients and also in a mouse model.

2024-05-06 | GSE247260 | GEO

S100A8 treatment on gene expression of human umbilical vascular endothelial cells.

2011-11-20 | GSE33768 | GEO