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Inhibiting the KIT-Src pathway to ensure differentiation of hematopoietic progenitor requires ARID4B

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148273 | GEO | 2021/11/06

REPOSITORIES: GEO

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Similar Datasets

Inhibiting the KIT-Src pathway to ensure differentiation of hematopoietic progenitor requires ARID4B [ChIP-seq]

Project description:Hematopoiesis is maintained by a highly regulated and hierarchical system, whereas aberrant control of hematopoiesis is the underlying cause of severe hematological diseases. Here, we demonstrate the indispensable role of ARID4B in fetal hematopoiesis that recruits Ezh2 to transcriptionally downregulate the expression of KIT during erythroid cell differentiation. Functional analyses reveal that the aberration of Arid4b inhibits fetal hematopoiesis at the multipotent progenitors (MPPs) stage, which reactivates the KIT-Src-family kinase (Src) pathway and leads to pre-mature erythroblast proliferation. The differentiation defect caused by ARID4B aberration could be counteracted by the Src inhibitor PP2 or by KIT knockdown. In summary, we identify ARID4B as a master regulator in the KIT-Src pathway, thus providing a fundamental insight in hematopoiesis and stem cell regulation.

2021-11-09 | GSE148272 | GEO

Inhibiting the KIT-Src pathway to ensure differentiation of hematopoietic progenitor requires ARID4B [RNA-seq]

2021-11-09 | GSE148269 | GEO

Inhibiting the KIT-Src pathway to ensure differentiation of hematopoietic progenitor requires ARID4B

Project description:Inhibiting the KIT-Src pathway to ensure differentiation of hematopoietic progenitor requires ARID4B

| PRJNA623628 | ENA

Inhibiting the KIT-Src pathway to ensure differentiation of hematopoietic progenitor requires ARID4B [RNA-seq]

Project description:Inhibiting the KIT-Src pathway to ensure differentiation of hematopoietic progenitor requires ARID4B [RNA-seq]

| PRJNA623630 | ENA

Inhibiting the KIT-Src pathway to ensure differentiation of hematopoietic progenitor requires ARID4B [ChIP-seq]

Project description:Inhibiting the KIT-Src pathway to ensure differentiation of hematopoietic progenitor requires ARID4B [ChIP-seq]

| PRJNA623629 | ENA

Differentiation of fetal hematopoietic stem cells requires ARID4B to restrict autocrine KITLG/KIT-Src signaling.

Project description:Balance between the hematopoietic stem cell (HSC) duality to either possess self-renewal capacity or differentiate into multipotency progenitors (MPPs) is crucial for maintaining homeostasis of the hematopoietic stem/progenitor cell (HSPC) compartment. To retain the HSC self-renewal activity, KIT, a receptor tyrosine kinase, in HSCs is activated by its cognate ligand KITLG originating from niche cells. Here, we show that AT-rich interaction domain 4B (ARID4B) interferes with KITLG/KIT signaling, consequently allowing HSC differentiation. Conditional Arid4b knockout in mouse hematopoietic cells blocks fetal HSC differentiation, preventing hematopoiesis. Mechanistically, ARID4B-deficient HSCs self-express KITLG and overexpress KIT. As to downstream pathways of KITLG/KIT signaling, inhibition of Src family kinases rescues the HSC differentiation defect elicited by ARID4B loss. In summary, the intrinsic ARID4B-KITLG/KIT-Src axis is an HSPC regulatory program that enables the differentiation state, while KIT stimulation by KITLG from niche cells preserves the HSPC undifferentiated pool.

| S-EPMC8722094 | biostudies-literature

Hematopoietic stem and progenitor cell proliferation and differentiation requires the trithorax protein Ash2l.

Project description:Post-translational modifications of core histones participate in controlling the expression of genes. Methylation of lysine 4 of histone H3 (H3K4), together with acetylation of H3K27, is closely associated with open chromatin and gene transcription. H3K4 methylation is catalyzed by KMT2 lysine methyltransferases that include the mixed-lineage leukemia 1-4 (MLL1-4) and SET1A and B enzymes. For efficient catalysis, all six require a core complex of four proteins, WDR5, RBBP5, ASH2L, and DPY30. We report that targeted disruption of Ash2l in the murine hematopoietic system results in the death of the mice due to a rapid loss of mature hematopoietic cells. However, lin-Sca1+Kit+ (LSK) cells, which are highly enriched in hematopoietic stem and multi-potent progenitor cells, accumulated in the bone marrow. The loss of Ash2l resulted in global reduction of H3K4 methylation and deregulated gene expression, including down-regulation of many mitosis-associated genes. As a consequence, LSK cells accumulated in the G2-phase of the cell cycle and were unable to proliferate and differentiate. In conclusion, Ash2l is essential for balanced gene expression and for hematopoietic stem and multi-potent progenitor cell physiology.

| S-EPMC6547667 | biostudies-literature

Kit-Shp2-Kit signaling acts to maintain a functional hematopoietic stem and progenitor cell pool.

Project description:The stem cell factor (SCF)/Kit system has served as a classic model in deciphering molecular signaling events in the hematopoietic compartment, and Kit expression is a most critical marker for hematopoietic stem cells (HSCs) and progenitors. However, it remains to be elucidated how Kit expression is regulated in HSCs. Herein we report that a cytoplasmic tyrosine phosphatase Shp2, acting downstream of Kit and other RTKs, promotes Kit gene expression, constituting a Kit-Shp2-Kit signaling axis. Inducible ablation of PTPN11/Shp2 resulted in severe cytopenia in BM, spleen, and peripheral blood in mice. Shp2 removal suppressed the functional pool of HSCs/progenitors, and Shp2-deficient HSCs failed to reconstitute lethally irradiated recipients because of defects in homing, self-renewal, and survival. We show that Shp2 regulates coordinately multiple signals involving up-regulation of Kit expression via Gata2. Therefore, this study reveals a critical role of Shp2 in maintenance of a functional HSC/progenitor pool in adult mammals, at least in part through a kinase-phosphatase-kinase cascade.

| S-EPMC3109710 | biostudies-literature

ATP/IL-33-Co-Sensing by Mast Cells (MCs) Requires Activated c-Kit to Ensure Effective Cytokine Responses

Project description: Not available

| S-EPMC10705958 | biostudies-literature

Tracing Hematopoietic Progenitor Cell Neutrophilic Differentiation via Raman Spectroscopy.

Project description:A major challenge to experimental studies and therapeutic uses of hematopoietic stem cells (HSC) is the limited options for analytical tools that can reliably resolve functional differences in heterogeneous HSC subpopulations at the single cell level. Currently available methods require the use of external labels and/or separate clonogenic and transplantation assays to identify bona fide stem cells, necessitating the harvest of bulk cell populations and long incubation times that obscure how individual HSCs dynamically respond to exogenous and endogenous stimuli. In this study, we employ Raman spectroscopy to noninvasively resolve the dynamics of individual differentiating hematopoietic progenitor cells during the course of neutrophilic differentiation. We collected Raman peaks of individual cells daily over the course of 14-day neutrophilic differentiation. Principal component analysis (PCA) of the Raman peaks revealed spectral differences between individual cells during differentiation that were strongly correlated with changes in the nucleus shape and surface antigen expression, the primary traditional means of monitoring neutrophilic differentiation. Additionally, our results were consistently reproducible in independent rounds of neutrophilic differentiation, as demonstrated by our partial least-squares discriminant analysis (PLS-DA) of the Raman spectral information that predicted the degree of neutrophilic differentiation with high sensitivity and specificity. Our findings highlight the utility and reliability of Raman spectroscopy as a robust molecular imaging tool to monitor the kinetics of HSC differentiation patterns.

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