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Analysis of Aiolos and OBF-1 deletions in bone marrow from 7 week old mice

ABSTRACT: The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes l5l5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the l5l5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function. OBF-1 or Aiolos or both were deleted and the gene expression profiles for these animals investigated using Affymetrix arrays Keywords: Genetic modifications

ORGANISM(S): Mus musculus

PROVIDER: GSE12356 | GEO | 2008/11/03

SECONDARY ACCESSION(S): PRJNA113185

REPOSITORIES: GEO

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Transcription profiling of mouse bone marrow with Aiolos and OBF-1 deletions from 7 week old mice

Project description:The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes l5l5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the l5l5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function. OBF-1 or Aiolos or both were deleted and the gene expression profiles for these animals investigated using Affymetrix arrays Experiment Overall Design: Two control wildtype animals, then duplicates for each of the single Aiolos or OBF-1 mutants and further duplicates for the Aiolos/OBF-1 double mutants

2008-11-13 | E-GEOD-12356 | biostudies-arrayexpress

A Variant in Human AIOLOS Impairs Adaptive Immunity by Interfering with IKAROS

Project description:A missense mutation (G158R) in Aiolos, encoded by Ikzf3 gene, resulted in defective generation of B cells in mice. Pre-B cells were profoundly decreased in homozygous mutant mice. Heterozygous mutant mice showed milder B cell developmental defects, and B cells in the secondary lymphoid organs decreased. Genome-wide binding of Aiolos and Ikaros were altered in the thymus of homozygous Ikzf3 G158R mice. Our findings indicate that Aiolos-G158R hinders B cell development by interfering Ikaros' function via formation of heterodimers. A heterozygous missense variant (G159R) in AIOLOS, encoded by IKZF3 gene, resulted in impaired adaptive immunity, which predominantly manifested as profound B cell developmental defect. Genome-wide binding of wild-type AIOLOS and AIOLOS G159R mutant were examined in IKZF3 knock-out human pre-B cell line NALM-6, retrovirally transduced with doxycycline inducible wild-type AIOLOS or AIOLOS G159R. Changes in genome-wide binding and binding motif were observed for AIOLOS G159R mutant.

2021-05-01 | GSE167487 | GEO

A missense mutation in AIOLOS causes B cell deficiency by interfering with IKAROS

Project description:A missense mutation (G158R) in Ikzf3 gene resulted in defective generation of B cells in mice. Pre-B cells were profoundly decreased in homozygous mutant mice. Heterozygous mutant mice showed milder B cell developmental defects, and decreased B cells in the secondary lymphoid organs were observed. Ikzf3 encodes Aiolos, which makes heterodimer with Ikaros. Our findings indicate that the loss-of-function mutation in Aiolos hinders B cell development by interfering Ikaros' function via formation of heterodimers.

2022-02-16 | GSE126778 | GEO

Aiolos regulated genes in A549, lung carcinoma cells

Project description:Analysis of transcriptional profiling change comparing A549 cells expressing control empty vector and A549 cells expressing Aiolos. Results provide insight into molecular mechanisms underlying functional consequence of ectopic expression of Aiolos in solid cancer cells. Two-condition experiment, A549-empty vs. A549-Aiolos cells. Biological replicates: 3 control, 3 transfected, independently grown and harvested. One replicate per array.

2013-09-13 | E-GEOD-50812 | biostudies-arrayexpress

RAG-mediated DNA double strand breaks activate a cell-type-specific checkpoint to inhibit pre-B cell receptor signals

Project description:Pre-B cell receptor (pre-BCR) signals initiate immunoglobulin light (Igl) chain gene assembly leading to RAG-mediated DNA double-strand breaks (DSBs). These signals also promote cell cycle entry, which could cause aberrant DSB repair and genome instability in pre-B cells. Here we show that RAG DSBs inhibit pre-BCR signals through the ATM- and NF-κB2-dependent induction of SPIC, a hematopoietic-specific transcriptional repressor. SPIC inhibits expression of the SYK tyrosine kinase and BLNK adaptor to prevent the pre-BCR from inducing additional Igl chain gene rearrangements and driving pre-B cells with RAG DSBs into cycle. We propose that pre-B cells toggle between pre-BCR signals and this RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes.

2016-01-13 | GSE67854 | GEO

BCR heavy and light chain repertoire sequencing of pertitoneal cavity B-1a cells from wild-type and Igll1 knockout mice

Project description:We report that B-1a cells develop in a surrogate light chain independent context. As a consequence, the precursor B-1a cell population avoids a pre-BCR positive selection stage. To confirm that the B-1a cells generated in this manner repersent a bonafide B-1a cell compartment, we did NGS on BCR rearrangements to assess the repertoire diversity. We find that as a whoile, B-1a cell repertoire that develop in Igll1 kncokout mice are similar compared to wild-type. This supports our findings that B-1a cells develop properly in the absence of surrogate light chain.

2018-01-15 | GSE104111 | GEO

Gene expression data of interleukin-7-dependent and BCR-ABL1-transformed pre-B cells

Project description:This analysis focused on identifying factors that protect pre-B cells against DNA double strand break (DSB)-mediated DNA damage stress during pre-B cell differentiation. Differentiation of pre-B cells including immunoglobulin light chain gene recombination were performed by withdrawal of interleukin-7 (IL-7) from IL-7-dependent murine pre-B cells or by inhibition of the BCR-ABL1 kinase activity in BCR-ABL1-transformed pre-B cells. The BCR-ABL1 kinase inhibitor STI571 (Imatinib) was used for the inhibition of BCR-ABL1.

2010-05-10 | GSE21664 | GEO

Transcription profiling of mouse IRF4,8 null pre-B cells treated with ILF7 reveals convergent molecular pathways that induce immunoglobulin light-chain recombination

Project description:Productive rearrangement of the immunoglobulin heavy chain locus triggers a major developmental checkpoint that promotes limited clonal expansion of pre-B cells, culminating in cell cycle arrest and rearrangement of the kappa (Îº) or lambda (Î») light-chain loci. B lineage cells lacking the related transcription factors IRF-4 and IRF-8 undergo a developmental arrest at the cycling pre-B cell stage and are blocked for light-chain recombination. Using Irf-4,8-/- pre-B cells we demonstrate that two pathways converge to synergistically drive light-chain rearrangement, a process that is not simply activated by cell cycle exit. One pathway is directly dependent on IRF-4, whose expression is elevated by pre-BCR signaling. IRF-4 targets the Îº 3â² and Î» enhancers to increase locus accessibility and positions a kappa allele away from pericentromeric heterochromatin. The other pathway is triggered by attenuation of IL-7 signaling and results in activation of the Îº intronic enhancer via binding of the transcription factor, E2A. Intriguingly, IRF-4 regulates the expression of CXCR4 and promotes the migration of pre-B cells in response to the chemokine CXCL12. We propose that IRF-4 coordinates the two pathways regulating light-chain recombination by positioning pre-B cells away from IL-7 expressing stromal cells. We used microarrys to identify the changes in gene expression under different levels of the cytokine IL-7 and after rescue of genetic defect. Experiment Overall Design: IRF4,8 null pre-B cells were cultures in the indicated conditions prior to RNA isolation and hybridization to Affymetrix arrays.

2008-06-11 | E-GEOD-10273 | biostudies-arrayexpress

RAG-mediated DNA double strand breaks activate a cell-type-specific checkpoint to inhibit pre-B cell receptor signals

Project description:Pre-B cell receptor (pre-BCR) signals initiate immunoglobulin light (Igl) chain gene assembly leading to RAG-mediated DNA double-strand breaks (DSBs). These signals also promote cell cycle entry, which could cause aberrant DSB repair and genome instability in pre-B cells. Here we show that RAG DSBs inhibit pre-BCR signals through the ATM- and NF-ÎºB2-dependent induction of SPIC, a hematopoietic-specific transcriptional repressor. SPIC inhibits expression of the SYK tyrosine kinase and BLNK adaptor to prevent the pre-BCR from inducing additional Igl chain gene rearrangements and driving pre-B cells with RAG DSBs into cycle. We propose that pre-B cells toggle between pre-BCR signals and this RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes. Three independent IL-7 cultures for each genotype (Rag1-/-:Î¼IgH:Bcl2, Art-/-:Î¼IgH:Bcl2 and Art-/-:Nfkb2-/-:Î¼IgH:Bcl2) were withdrawn from IL-7 for 2 days. RNA was isolated using RNeasy (Qiagen). Gene expression profiling was performed using Illumina MouseRef-8 expression microarrays.

2016-01-13 | E-GEOD-67854 | biostudies-arrayexpress

Pre-BCR Signaling induce IgK Locus Accessibility by functional redistribution of Enhancer-mediated chromatin Interactions

Project description:During B cell development the precursor B cell receptor (pre-BCR) checkpoint is thought to increase immunoglobulin k light chain (Igk) locus accessibility to the V(D)J recombinase. Accordingly, pre-B cells lacking the pre-BCR signaling molecules Btk or Slp65 showed reduced germline Vk transcription. To investigate whether pre-BCR signaling modulates Vk accessibility through enhancer-mediated Igk locus topology, we performed chromosome conformation capture and sequencing analyses. These revealed that already in pro-B cells the k enhancers robustly interact with the ~3.2 Mb Vk region and its flanking sequences. Analyses in wild-type, Btk and Slp65 single and double-deficient pre-B cells demonstrated that pre-BCR signaling reduces interactions of both enhancers with Igk locus flanking sequences and increases interactions of the 3â??k enhancer with Vk genes. Remarkably, pre-BCR signaling does not significantly affect interactions between the intronic enhancer and Vk genes, which are already robust in pro-B cells. Both enhancers interact most frequently with highly used Vk genes, which are often marked by transcription factor E2a. We conclude that the k enhancers interact with the Vk region already in pro-B cells and that pre-BCR signaling induces accessibility through a functional redistribution of long-range chromatin interactions within the Vk region, whereby the two enhancers play distinct roles. We performed genome-wide expression profiling of FACS-purified B220+CD19+ pre-B cell fractions from wild-type (WT), Btk and Slp65 single and double deficient VH81x transgenic Rag1-/- mice (n=4 of each genotype). In these experiments non-VH81x transgenic Rag1-/- pro-B cells served as controls (n=3).

2014-03-21 | E-GEOD-53896 | biostudies-arrayexpress

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