Gene expression profile induced by Imatinib
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE35559 | GEO | 2012/02/08
SECONDARY ACCESSION(S): PRJNA152679
REPOSITORIES: GEO
Similar Datasets
Project description:Activation-induced cytidine deaminase (AID) is essential for class switch recombination (CSR) and somatic hypermutation (SHM). Its deregulated expression acts as a genomic mutator that can contribute to the development of various malignancies. During treatment with imatinib mesylate (IM), patients with chronic myeloid leukemia (CML) often develop hypogammaglobulinemia, the mechanism of which has not yet been clarified. Here, we provide evidence that CSR upon B cell activation is apparently inhibited by IM through downregulation of AID. Furthermore, expression of E2A, a key transcription factor for AID induction, was markedly suppressed by IM. These results elucidate not only the underlying mechanism of IM-induced hypogammaglobulinemia but also its potential efficacy as an AID suppressor. We investigated that class switch recombination(CSR) upon B cell activation is apparently inhibited by imatinib mesylate(IM) through downregulation of activation-induced cytidine deaminase(AID). Furthermore, expression of E2A was markedly suppressed by IM. To elucidate the more detailed pathway, we performed the microarray analysis. Microarray analysis was performed on splenocytes cultured for 72 h in the presence or absence of 10 µM Imatinib. The mouse splenocytes were cultured for 72 h with or without 10 µM Imatinib (IM) in conditioning medium containing IL-4 and LPS. RNA from 1X10^6 splenocytes used for microarray analysis was isolated using the RNeasy Mini Kit (50) (Qiagen, Hilden, Germany). Gene expression microarray analysis was performed using one-color microarray-based gene-expression analysis (Agilent Technologies, Santa Clara, CA, USA) according to the manufacturer’s instructions. After scanning, expression values for the genes were determined using GeneSpringGX software.
2012-02-08 | E-GEOD-35559 | biostudies-arrayexpress
Project description:Most human B cell lymphomas (B-NHL) are derived from germinal centers (GCs), the structure where B-cells undergo class switch recombination (CSR) and somatic hypermutation (SHM) and are selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant somatic hypermutation, which appear to arise from mistakes occurring during CSR and SHM. To ascertain the role of CSR and SHM in lymphomagenesis, we crossed three oncogene-driven (MYC, BCL6, MYC/BCL6) mouse models of B cell lymphoma with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both processes. We show that AID deficiency prevents BCL6-dependent, GC-derived B-NHL, while it has no impact on the formation of MYC-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of both CSR- and SHM-mediated structural alterations, including cMYC-IgH chromosomal translocations and aberrant SHM. These results demonstrate that AID is required for GC-derived lymphomagenesis, providing direct support to the notion that errors in AID-mediated antigen-receptor gene modification events represent major contributors to the pathogenesis of human B-NHL. Keywords: Phenotypic characterization of tumors developing in oncogene-driven mouse models of lymphomas
2007-11-01 | GSE9249 | GEO
Project description:Activation-induced cytidine deaminase (AID) initiates both somatic hypermutation (SHM) for antibody affinity maturation and DNA breakage for antibody class switch recombination (CSR) via transcription-dependent cytidine deamination of single stranded DNA targets. While largely specific for immunglobulin genes, AID also acts on a limited set of off-targets, generating oncogenic translocations and mutations that contribute to B cell lymphoma. How AID is recruited to off-targets has been a long-standing mystery. Based on deep GRO-Seq studies of mouse and human B lineage cells activated for CSR or SHM, we report that most robust AID off-target translocations occur within highly focal regions of target genes in which sense and antisense transcription converge. Moreover, we found that such AID-targeting "convergent" transcription arises from antisense transcription that emanates from Super-Enhancers within sense transcribed gene bodies. Our findings provide a mechanistic explanation for AID off-targeting to a small subset of mostly lineage-specific genes in activated B cells. We performed GRO-Seq and H3K27Ac ChIP-Seq with different B lineage cell types and MEF cells to find the signatures associated with AID targeting.
2014-12-04 | E-GEOD-62296 | biostudies-arrayexpress
Project description:Class switch recombination (CSR) and somatic hypermutation (SHM) are antibody gene diversification reactions occurring in mature B cells that are essential for protective humoral immunity. CSR and SHM are initiated following activation by the antigen, and are dependent on efficient induction of activation-induced cytidine deaminase (AID). Therefore, mature B cell viability and fitness are crucial to mount effective immune responses. Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation, and ensures efficient antibody diversification by promoting their survival and optimal function.
2020-06-19 | GSE141876 | GEO
Project description:During germinal center (GC) reactions, activated B cells undergo clonal expansion and functional maturation to produce high-affinity antibodies, and differentiate into plasma and memory cells, accompanied with class-switching recombination (CSR) and somatic hypermutation (SHM). Activation-induced deaminase (AID) is responsible for both CSR and SHM in GC B cells. Transcriptional mechanisms underlying AID regulation and GC B cell reactions are still not well understood. Here, we show that expression of Ascl2 transcription factor is upregulated in GC B cells. Ectopic expression of Ascl2 promotes GC B cell development and enhances antibody production as well as affinity maturation. Conversely, deletion of Ascl2 in B cells impairs the germinal center response. Genome-wide analysis reveals that Ascl2 directly regulates GC B cell-related genes, including AID; ectopic expression of AID in Ascl2-deficient B cells rescues their antibody defects. Thus, Ascl2 regulates AID transcription and promotes germinal center B cell responses.
2021-03-30 | GSE169416 | GEO
Project description:Activation-induced cytidine deaminase (AID) initiates both somatic hypermutation (SHM) for antibody affinity maturation and DNA breakage for antibody class switch recombination (CSR) via transcription-dependent cytidine deamination of single stranded DNA targets. While largely specific for immunglobulin genes, AID also acts on a limited set of off-targets, generating oncogenic translocations and mutations that contribute to B cell lymphoma. How AID is recruited to off-targets has been a long-standing mystery. Based on deep GRO-Seq studies of mouse and human B lineage cells activated for CSR or SHM, we report that most robust AID off-target translocations occur within highly focal regions of target genes in which sense and antisense transcription converge. Moreover, we found that such AID-targeting "convergent" transcription arises from antisense transcription that emanates from Super-Enhancers within sense transcribed gene bodies. Our findings provide a mechanistic explanation for AID off-targeting to a small subset of mostly lineage-specific genes in activated B cells.
2014-12-04 | GSE62296 | GEO
Project description:Activation-induced cytidine deaminase (AID) plays a vital role in adaptive immunity by enabling class switch recombination (CSR) and somatic hypermutation (SHM). While many molecular factors affect AID targeting and function, mounting evidence implicates G-quadruplex (G4) nucleic acid structures as critical effectors of AID biology. To examine the function of AID-G4 binding in vivo, we generated a knock-in mouse with a mutation in Aicda (AIDG133V) that disrupts AID-G4 binding without altering DNA deaminase activity. AIDG133V mice completely lack CSR and SHM, modeling the pathology of hyper-IgM syndrome patients with an orthologous mutation. ChIP-sequencing experiments reveal a broad defect in AIDG133V chromatin localization, implicating AID-G4 binding in genome-wide AID targeting. We find that major histocompatibility complex (MHC) class II genes are AID targets, and that increased AID expression in diffuse large B-cell lymphomas (DLBCLs) correlates with decreased MHC class II expression. Given that loss of MHC class II expression in DLBCLs is highly correlated with adverse outcomes, AID-dependent gene regulation may provide a novel therapeutic target.
2020-10-14 | GSE136959 | GEO
Project description:Secondary diversification of antibodies through somatic hypermutation (SHM) and class switch recombination (CSR) is a critical component of the immune response. Activation-induced deaminase (AID) initiates both processes by deaminating cytosine residues in immunoglobulin genes. The resulting U:G mismatch can be processed by alternative pathways to give rise to a mutation (SHM) or a DNA double-strand break (CSR). Central to this processing is the activity of uracil-N-glycosylase (UNG), an enzyme normally involved in error-free base excision repair. We used next generation sequencing to analyze the contribution of UNG to the resolution of AID-induced lesions. Loss- and gain-of-function experiments showed that UNG activity can promote both error-prone and high fidelity repair of U:G lesions. Unexpectedly, the balance between these alternative outcomes was influenced by the sequence context of the deaminated cytosine, with individual hotspots exhibiting higher susceptibility to UNG-triggered error-free or error-prone resolution. These results reveal UNG as a new molecular layer that shapes the specificity of AID-induced mutations and may provide new insights into the role of AID in cancer development. Next Generation Sequencing analysis of mutations introduced by AID in activated B lymphocytes from WT and UNG-/- mice (n=4). Activated B cells from AID-/- mice (n=2) were used as negative controls.
2012-07-04 | E-GEOD-39114 | biostudies-arrayexpress
Project description:The transcription factor Bach2 is required for germinal center formation and somatic hypermutation (SHM) of immunoglobulins, both central to an efficient antibody-mediated immune response. Activation-induced cytidine deaminase (AID) initiates SHM and CSR in germinal centers and has potential to induce human B cell lymphoma. To understand the role of Bach2 in AID-mediated immunoglobulin gene diversification processes, we established a Bach2-deficient DT40 B cell line. We show that in addition to allowing SHM, Bach2 drives immunoglobulin gene conversion (GCV), an important AID-dependent antibody gene diversification process. We demonstrate that Bach2 promotes GCV by increasing the expression of AID. Importantly, we found that the regulation of AID is independent of Blimp-1 and that Bach2-deficient cells have altered expression of several genes regulating AID expression, stability and function. These results demonstrate that Bach2 has a previously unappreciated role in the production of high-affinity antibodies.
2017-03-27 | GSE92430 | GEO
Project description:H3K4me3 plays a critical role in the activation-induced cytidine deaminase (AID)-induced DNA cleavage of switch (S) regions in the immunoglobulin heavy chain (IgH) locus during class-switch recombination (CSR). The histone chaperone complex facilitates chromatin transcription (FACT) is responsible for forming H3K4me3 at AID target loci. Histone chaperone suppressor of Ty6 (Spt6) also participates in regulating H3K4me3 for CSR and for somatic hypermutation (SHM) in AID target loci. H3K4me3 loss was correlated with defects in AID-induced DNA breakage and reduced mutation frequencies in IgH loci, in both S and variable regions, and in non-IgH loci, such as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and small nucleolar RNA host gene 3 (SNHG3). Global gene expression analysis revealed that Spt6 can act as both a positive and negative transcriptional regulator in B cells, affecting approximately 5% of the genes that includes suppressor of Ty4 (Spt4) and AID. Interestingly, Spt6 regulates CSR and AID expression through two distinct histone modification pathways, H3K4me3 and H3K36me3, respectively. Spt6 is a unique histone chaperone, capable of regulating the histone epigenetic state of both AID targets and the AID locus. CH12F3-2A cells were transfected with control and Spt6 siRNAs; 24h later, cells were stimulated with CIT to induce CSR. Total RNA was extracted from control and Spt6 siRNA treated cells for mRNA expression profiling.
2013-02-01 | E-GEOD-35334 | biostudies-arrayexpress