Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

IL-7 receptor signaling drives human B-cell precursor differentiation and expansion

ABSTRACT: Whereas absence of interleukin 7 (IL-7) signaling completely abrogates T and B lymphopoiesis in mice, severe combined immunodeficiency patients with mutations in the IL-7 receptor α chain still generate peripheral blood B cells. Consequently, human B lymphopoiesis has been thought to be independent of IL-7 signaling. Using flow cytometric analysis and single-cell RNA sequencing of bone marrow samples of IL-7 receptor α chain-deficient patients and healthy controls in combination with in vitro modeling of human B-cell differentiation, we demonstrate that IL-7 receptor signaling has a crucial role in human B lymphopoiesis. IL-7 drives proliferation and expansion of early B-cell progenitors, but not of pre-BII large cells. In addition, IL-7 has a limited role in the prevention of cell death. Furthermore, IL-7 guides cell fate decisions by enhancing the expression of BACH2, EBF1, and PAX5, which jointly orchestrate specification and commitment of early B-cell progenitors. In line with this observation, early B-cell progenitors of IL-7Rα-deficient patients still expressed myeloid-specific genes. Collectively, our results unveil a thus-far unknown role for IL-7 signaling in promoting the B-lymphoid fate and expanding early human B-cell progenitors, while defining important differences between mice and humans. Our results have implications for hematopoietic stem cell transplantation strategies in patients with T- B+ severe combined immunodeficiency and provide insights into the role of IL-7 receptor signaling in leukemogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214693 | GEO | 2023/07/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Expression data from B220+ Hspa9+/+ and Hspa9+/- CFU-PreB colonies isolated on Day 7 of culture

Project description:CFU-PreB colonies are reduced in number and size in Hspa9+/- mice compared to wildtype littermates. We compared the expression profiles of these colonies to gain insight into the mechanism driving this difference. HSPA9 is located on chromosome 5q31.2 in humans, a region that is commonly deleted in patients with myeloid malignancies [del(5q)], including myelodysplastic syndromes (MDS). HSPA9 expression is reduced by 50% in patients with del(5q)-associated MDS, consistent with haploinsufficient levels. Zebrafish mutants and knockdown studies in human and mouse cells have implicated a role for HSPA9 in hematopoiesis. To comprehensively evaluate the effects of Hspa9 haploinsufficiency on hematopoiesis, we generated an Hspa9 knockout mouse model. While homozygous knockout of Hspa9 is embryonic lethal, mice with heterozygous deletion of Hspa9 (Hspa9+/-) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/- mice have normal basal hematopoiesis and do not develop MDS. However, Hspa9+/- mice have a cell-intrinsic reduction in bone marrow CFU-PreB colony formation without alterations in the number of B-cell progenitors in vivo, consistent with a functional defect in Hspa9+/- B-cell progenitors. We further reduced Hspa9 expression (<50%) using RNAi and observe reduced B-cell progenitors in vivo, indicating that appropriate levels (≥50%) of Hspa9 are required for normal B-lymphopoiesis in vivo. Knockdown of Hspa9 in an IL-7 dependent mouse B-cell line reduced Stat5 phosphorylation following IL-7 receptor stimulation, supporting a role for Hspa9 in Stat5 signaling in B-cells. Collectively, these data implicate a role for Hspa9 in B-lymphopoiesis and Stat5 activation downstream of IL-7 signaling. Bone marrow cells from 5 Hspa9+/+ and 5 Hspa9+/- mice were independently cultured in CFU-PreB methylcellulose medium for 7 days. PreB colonies were isolated and B220+ cells were flow sorted for RNA isolation.

2015-02-04 | E-GEOD-65588 | biostudies-arrayexpress

Expression data from B220+ Hspa9+/+ and Hspa9+/- CFU-PreB colonies isolated on Day 7 of culture

2015-02-04 | GSE65588 | GEO

IGH analysis in pro-B cells with H3K4me3, H3K4me2 and H3K9ac

Project description:STAT5 and IL-7 signaling are thought to control B-lymphopoiesis by regulating key transcription factor genes and activating VH gene segments at the Igh locus. Using conditional mutagenesis, we demonstrate that transgenic Bcl2 expression rescued the development of Stat5-deleted pro-B cells by compensating for the loss of Mcl-1. Ebf1 and Pax5 expression as well as VH recombination were normal in Bcl2-rescued pro-B cells lacking STAT5 or IL-7Ra. In agreement with this finding, STAT5-expressing pro-B cells contained little or no active chromatin at most VH genes. In contrast, Igk rearrangements were increased in STAT5- or IL-7Ra-deficient pro-B cells, consistent with direct binding of STAT5 to the intronic iEk enhancer in wild-type pro-B cells. Hence, STAT5 and IL-7 signaling control cell survival and suppress premature Igk recombination in early B-lymphopoiesis. comparison of wt vs Rag2-/- pro-B cells

2010-07-28 | E-GEOD-18278 | biostudies-arrayexpress

CHD4 is essential for transcriptional repression and lineage progression in B lymphopoiesis [ATAC-seq]

Project description:Cell-lineage specification is a tightly regulated process that is dependent on appropriate expression of lineage- and developmental stage-specific transcriptional programs. Accessibility and inaccessibility of gene loci are controlled dynamically during cellular development. Here, we show that Chromodomain Helicase DNA-binding protein 4 (CHD4), a major ATPase/helicase subunit of Nucleosome Remodeling and Deacetylase Complexes (NuRD) in lymphocytes, is essential for specification of the early B cell lineage transcriptional program. In the absence of CHD4 in early B cell progenitors in vivo, B cell progenitors are arrested at an early pro-B-like stage of development, unresponsive to IL-7 receptor signaling and complete V(D)J rearrangements at Igh loci inefficiently. Importantly, CHD4-deficient B cells express a significant number of non-B cell lineage genes, including genes involved in the development of other hematopoietic lineages and neuronal cells. The absence of CHD4 increased chromatin accessibility at hundreds of these gene loci, suggesting that its ability to repress transcription by mobilizing nucleosomes and compacting chromatin is a barrier against inappropriate transcription. Together, our data demonstrate the importance of CHD4 in establishing and maintaining an appropriate transcriptome in early B lymphopoiesis via chromatin accessibility.

2019-04-30 | GSE123503 | GEO

CHD4 is essential for transcriptional repression and lineage progression in B lymphopoiesis [RNA-seq]

2019-04-30 | GSE123502 | GEO

B cell development requires discrete regulation by PTEN-PI3K and mTOR pathways and the intricate interplay with IL-7 r-Stat5 signaling

Project description:IL-7 r and Stat5 signaling drives early B lymphopoiesis, but it remains poorly understood how Stat5-dependent and independent pathways contribute to this process. We report the discrete effects of PI3K and mTOR signaling on Stat5 signaling and B cell development. PI3K was not engaged by IL-7 in pro-B cells but was actively suppressed by PTEN to ensure proper IL-7 r expression, Stat5 signaling and pro-B cell survival. Further, IL-7-mediated mTORC1 activation, which was uncoupled from PI3K signaling, orchestrated a unique program in early B cell development in a Stat5-independent but Myc-dependent manner. mTORC1 was also required for immunoglobulin heavy chain rearrangement and Myc-driven lymphomagenesis. Finally, mTORC2 was not essential for early B cell development but contributed to peripheral B cell maturation. Altogether, genetic dissection of PI3K, mTORC1, and mTORC2 reveals the distinct effects of these seemingly related pathways on B cell development and the intricate interplay between PI3K, mTOR and IL-7 r-Stat5 signaling.

2018-02-14 | GSE81844 | GEO

CXCR4 signaling directs Igk recombination and the molecular mechanisms of late B lymphopoiesis

Project description:In B lymphopoiesis, activation of the pre-B cell antigen receptor (pre-BCR) is associated with both cell cycle exit and Igk recombination. Yet, how the pre-BCR mediates these functions remains unclear. Herein, we demonstrate that the pre-BCR initiates a feed-forward IRF4-CXC Receptor 4 (CXCR4) amplification loop. ERK activation by CXCR4 then directs the development of small and immature B cells including orchestrating cell cycle exit, pre-BCR repression, Igk recombination and BCR expression. In contrast, escape from IL-7 and pre-BCR expression have only modest effects on B cell developmental transcriptional and epigenetic programs. These data demonstrate a direct and central role for CXCR4 in orchestrating late B cell lymphopoiesis. Furthermore, in the context of previous findings, our data provide a three-receptor system sufficient to recapitulate the essential features of B lymphopoiesis in vitro.

2019-06-18 | GSE129311 | GEO

PU.1 is required for the developmental progression of multipotent progenitors to common lymphoid progenitors.

Project description:The transcription factor PU.1 is a central regulator of hematopoiesis, required for the normal differentiation of the myeloid and lymphoid lineages. Due to its essential role in early development and the importance of PU.1 in regulating several defining markers of lymphoid progenitors, its precise function in early lymphopoiesis has remained unclear. Using conditional mutagenesis and alternative lineage identification strategies, we demonstrate the developmental stage restricted function for PU.1 in early lymphopoiesis. PU.1 was required for efficient generation of “lymphoid primed multipotent progenitors (LMPPs)” from hematopoietic stem cells and was essential for the subsequent formation of “common lymphoid progenitors (CLPs)”. In contrast, further differentiation into the B cell lineage was independent of PU.1. The function of PU.1 was dosage sensitive as loss of one allele decreased all stages of early lymphopoiesis. PU.1 expression mirrored its functional role during lineage differentiation. PU.1 peaked at LMPPs and was maintained in CLPs, before being down regulated in committed pro-B cells. Examination of the transcriptional changes in PU.1 conditionally deficient LSK cells revealed that PU.1 activates lymphoid and dendritic cell associated genes in LMPPs, while repressing genes normally expressed in neutrophils. These data identify PU.1 as a critical regulator of lymphoid priming and the transition between LMPPs and CLPs.

2017-08-14 | GSE89642 | GEO

IGH analysis in pro-B cells with H3K4me3, H3K4me2 and H3K9ac

2010-07-28 | GSE18278 | GEO

Dataset of spatiotemporal influences of interleukin IL-1 family cytokine: Interleukin-33 on cellular signal transduction pathways

Project description:Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines that play a central role in the regulation of immune responses. IL-33 signaling, from the early signaling events triggered by the ligand-activated receptor to result in activation of early and late signaling events, such as proteome changes. In this study, THP1 (monocyte) cell line model was stimulated with IL-33 (50 ng/ml) for varying duration (5, 10, 15, 30, 40, 60, 120 and 240 mins). We carried out in-depth proteomic analysis using high-resolution LC-MS/MS. Our analysis resulted in the identification of 64,030 peptides corresponding to 7947 protein groups. Differentially regulated proteins identified in this study could be targeted for developing an inflammatory immune response.

2022-02-17 | PXD024385 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data