CXCR4 signaling directs Igk recombination and the molecular mechanisms of late B lymphopoiesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA530792 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8844820.fastq.gz | Fastqsanger.gz | |||
| SRR8844830.fastq.gz | Fastqsanger.gz | |||
| SRR8844821.fastq.gz | Fastqsanger.gz | |||
| SRR8844831.fastq.gz | Fastqsanger.gz | |||
| SRR8844822.fastq.gz | Fastqsanger.gz |
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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
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. Here, we demonstrate that the pre-BCR initiates a feed-forward amplification loop mediated by the transcription factor interferon regulatory factor 4 and the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4). CXCR4 ligation by C-X-C motif chemokine ligand 12 activates the mitogen-activated protein kinase extracellular-signal-regulated kinase, which then directs the development of small pre- and immature B cells, including orchestrating cell cycle exit, pre-BCR repression, Igk recombination and BCR expression. In contrast, pre-BCR expression and escape from interleukin-7 have only modest effects on B cell developmental transcriptional and epigenetic programs. These data show 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.
| S-EPMC6754289 | biostudies-literature
Project description:B lymphopoiesis requires that immunoglobulin genes be accessible to RAG1-RAG2 recombinase. However, the RAG proteins bind widely to open chromatin, which suggests that additional mechanisms must restrict RAG-mediated DNA cleavage. Here we show that developmental downregulation of interleukin 7 (IL-7)-receptor signaling in small pre-B cells induced expression of the bromodomain-family member BRWD1, which was recruited to a specific epigenetic landscape at Igk dictated by pre–BCR-dependent Erk activation. BRWD1 enhanced RAG recruitment, increased gene accessibility and positioned nucleosomes 5? to each J? recombination signal sequence. BRWD1 thus targets recombination to Igk and places recombination within the context of signaling cascades that control B cell development. Our findings represent a paradigm in which,at any particular antigen-receptor locus, specialized mechanisms enforce lineage- and stage-specific recombination. ChIP-seq for 1 transcription factor and 2 histone modifications in flow purified mouse small pre-B cells. ATAC-seq and RNA-seq in WT and Brwd-Mut mouse flow purified small pre-B cells.
2015-08-24 | E-GEOD-63302 | biostudies-arrayexpress
Project description:B lymphopoiesis requires that immunoglobulin genes be accessible to RAG1-RAG2 recombinase. However, the RAG proteins bind widely to open chromatin, which suggests that additional mechanisms must restrict RAG-mediated DNA cleavage. Here we show that developmental downregulation of interleukin 7 (IL-7)-receptor signaling in small pre-B cells induced expression of the bromodomain-family member BRWD1, which was recruited to a specific epigenetic landscape at Igk dictated by pre–BCR-dependent Erk activation. BRWD1 enhanced RAG recruitment, increased gene accessibility and positioned nucleosomes 5′ to each Jκ recombination signal sequence. BRWD1 thus targets recombination to Igk and places recombination within the context of signaling cascades that control B cell development. Our findings represent a paradigm in which,at any particular antigen-receptor locus, specialized mechanisms enforce lineage- and stage-specific recombination.
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Project description:Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. We demonstrate in small pre-B cells, that the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 differentially regulated over 7000 genes including repressing proliferative and inducing differentiation programs. However, BRWD1 did not regulate expression of transcription factors required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations had B cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1-/- mice. These data indicate that in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B cell development.
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Project description:BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis
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Project description:Dynamic genome folding is important for V(D)J recombination at the immunoglobulin kappa (Igk) locus, which recombines Jk and Vk gene segments across a 3.2 Mb region in both deletional and inversional orientations. Chromatin loop extrusion and diffusion are considered two key mechanisms underlying Igk folding, but how they coordinate remains unclear. Here we show that CTCF is a key regulator coupling loop extrusion and diffusion during Igk V-J rearrangement, promoting recombination in both orientations across long genomic distances. Mechanistically, the CTCF N-terminus promotes long-range loop extrusion that facilitates distal Vk usage by stabilizing cohesin against WAPL release, and also forms loop barriers enabling chromatin diffusion for inversional Vk joining. In CTCF N-terminal-deficient B cells, defects in inversional Vk joining are not restored by WAPL depletion but are instead largely rescued by a dCas9-blockade targeted to the Vk-Jk intergenic region, mimicking the CTCF barrier. Our findings thus highlight how CTCF coordinates distinct genome-folding mechanisms through its dual roles in cohesin stabilization and extrusion barrier formation to ensure the generation of a diverse Igk repertoire.
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Project description:The goal of this study was to identify signalling molecules downstream of CXCR4 in breast cancer cells. For this purpose, we sorted CXCR4-positive and CXCR4-negative cells from MDA-MB-231 breast cancer cell line by flow cytometry and performed microarrays analysis. Three sets of samples, each in quadruplicate, were analyzed. These include CXCR4-positive subpopulation, CXCR4-positive subpopulation treated with SDF-1 (ligand for CXCR4, also called CXCL12) for one hour and CXCR4-negative subpopulation.
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Project description:Extended loop extrusion across the immunoglobulin heavy-chain (Igh) locus facilitates VH-DJH recombination in pro-B cells by aligning the VH and DJH segments for RAG-mediated cleavage. This cohesin-mediated process, resulting in global changes of the chromosome architecture in pro-B cells, depends on a 3-fold downregulation of the cohesin-release factor Wapl by Pax5-induced repression of the Wapl promoter. Here, we demonstrate that chromatin looping and VK-JK recombination at the Igk locus was insensitive to a 3-fold Wapl increase in pre-B cells. Given the equally low Wapl mRNA levels in pro-B and pre-B cells, the Wapl protein was unexpectedly expressed at a 2.2-fold higher level in pre-B cells compared to pro-B cells, which resulted in a distinct chromosomal architecture with normalized loop sizes in pre-B cells. High-resolution analysis of the Igk locus identified multiple internal loops, which likely juxtapose VK and JK elements to facilitate VK-JK recombination. The higher Wapl expression in Igm-transgenic pre-B cells prevented extended loop extrusion at the Igh locus, leading to recombination of only the 6 most 3’ proximal VH genes and to allelic exclusion of all other VH genes in pre-B cells. Hence, the different chromosomal architectures in pro-B and pre-B cells forced the Igh and Igk loci to assume distinct folding principles to undergo V gene recombination.
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