Homo sapiens
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REPOSITORIES: ENA
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Project description:Activation-induced cytidine deaminase (AID) is required for both somatic hypermutation (SHM) and class-switch recombination (CSR) in activated B cells. AID is also known to target non-immunoglobulin genes and introduce mutations or chromosomal translocations, eventually causing tumors. To identify as-yet-unknown AID targets, we screened early AID-induced DNA breaks using two independent genome-wide approaches. Along with known AID targets, this screen identified a set of novel genes (SNHG3, MALAT1, BCL7A, and CUX1), and confirmed that these new loci accumulated mutations as high as Ig locus after AID activation. Moreover, these genes share three important characteristics with the immunoglobulin gene: translocations in tumors, repetitive sequences and the epigenetic modification of chromatin by H3K4 trimethylation in the vicinity of cleavage sites.
2012-02-01 | GSE32027 | 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
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.
2013-02-01 | GSE35334 | GEO
Project description:Activation Induced Deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in germinal center (GC) B cells through the deamination of deoxycytidine residues (dC) into deoxyuridines (dU) in immunoglobulin (Ig) genes. Although AID has a strong preference for Ig genes, it can also target other genomic regions, giving rise to mutations or chromosomal translocations. Thus, understanding the specificity of AID has major implications for oncogenic transformation. However, approaching AID specificity has proved extremely challenging because AID deamination events occur at low frequencies. Here we have sequenced at very high depth >1500 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets. This has enabled for the first time to define the molecular features predictive of AID target specificity genome-wide. Furthermore, we identify the most highly mutated hotspot for AID activity described to date. We also find that Base Excision Repair (BER) and Mismatch Repair (MMR) systems, which are responsible for the resolution of AID deaminations, back-up each other to faithfully repair AID-induced lesions. Finally, our data establishes a novel link between AID mutagenic activity and malignant transformation.
2018-01-19 | GSE102944 | GEO
Project description:Novel N-terminal Glucocorticoid Receptor Isoforms with Unique Transcriptional Target Genes
| PRJNA91587 | ENA
Project description:Programmed mutagenesis of the immunoglobulin locus of B-lymphocytes during class switch recombination and somatic hypermutation requires RNA polymerase II (RNA polII) transcription complex dependent targeting of the DNA mutator, Activation Induced cytidine Deaminase (AID). AID deaminates cytidine residues on substrate sequences in the immunoglobulin (Ig) locus via a transcription-dependent mechanism and this activity is stimulated by the RNA polII stalling co-factor Spt5 and the eleven-subunit cellular non-coding RNA 3’-5’ exonucleolytic processing complex, RNA exosome. The mechanism by which the RNA exosome recognizes immunoglobulin locus RNA substrates to stimulate AID DNA deamination activity on its in vivo substrate sequences is an important question. Here we report that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII by a ubiquitination event leading to generation of 3’-end free RNA exosome RNA substrates at the Ig locus and other AID target sequences genome-wide. Using highthrough-out RNA sequencing technology, we find that lack of Nedd4 activity in B cells leads to accumulation of RNA exosome substrates at AID target genes. Moreover, we find that Nedd4-deficient B cells are inefficient in undergoing class switch recombination. Taken together, our study links non-coding RNA processing following RNA polymerase II pausing with regulation of the mutator AID protein. Our study also identifies Nedd4 as a regulator of non-coding RNA that are generated by stalled RNA polII genome-wide. Splenic B cells from Nedd4+/+ and Nedd4-/- B cells fetal liver chimeric mice were were stimulated in culture for IgG1 CSR. Total RNA was isolated and evaluated with whole genome RNA-seq
2013-08-07 | E-GEOD-49027 | biostudies-arrayexpress
Project description:Programmed mutagenesis of the immunoglobulin locus of B-lymphocytes during class switch recombination and somatic hypermutation requires RNA polymerase II (RNA polII) transcription complex dependent targeting of the DNA mutator, Activation Induced cytidine Deaminase (AID). AID deaminates cytidine residues on substrate sequences in the immunoglobulin (Ig) locus via a transcription-dependent mechanism and this activity is stimulated by the RNA polII stalling co-factor Spt5 and the eleven-subunit cellular non-coding RNA 3’-5’ exonucleolytic processing complex, RNA exosome. The mechanism by which the RNA exosome recognizes immunoglobulin locus RNA substrates to stimulate AID DNA deamination activity on its in vivo substrate sequences is an important question. Here we report that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII by a ubiquitination event leading to generation of 3’-end free RNA exosome RNA substrates at the Ig locus and other AID target sequences genome-wide. Using highthrough-out RNA sequencing technology, we find that lack of Nedd4 activity in B cells leads to accumulation of RNA exosome substrates at AID target genes. Moreover, we find that Nedd4-deficient B cells are inefficient in undergoing class switch recombination. Taken together, our study links non-coding RNA processing following RNA polymerase II pausing with regulation of the mutator AID protein. Our study also identifies Nedd4 as a regulator of non-coding RNA that are generated by stalled RNA polII genome-wide.
2013-08-07 | GSE49027 | GEO
Project description:The antibody gene mutator AID promiscuously damages oncogenes and B cell identity genes leading to chromosomal translocations and tumorigenesis. Why non-immunoglobulin loci are susceptible to AID activity is unknown. Here we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome, but are predominantly clustered within super-enhancers. Unexpectedly, in these domains AID deaminates highly active promoters and eRNA+ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.
2014-12-04 | GSE62063 | GEO
Project description:Activation-induced cytidine deaminase (AID) mediates class switching by binding to a small fraction of single-stranded DNA (ssDNA) to diversify the antibody repertoire. The precise mechanism for highly selective AID targeting in the genome has remained elusive. Here, we report an RNA-binding protein, ROD1 (also known as PTBP3), that is both required and sufficient to define AID-binding sites genome-wide in activated B cells. ROD1 interacts with AID via an ultraconserved loop, which proves to be critical for the recruitment of AID to ssDNA using bi-directionally transcribed nascent RNAs as stepping stones. Strikingly, AID-specific mutations identified in human patients with hyper-IgM syndrome type 2 (HIGM2) completely disrupt the AID interacting surface with ROD1, thereby abolishing the recruitment of AID to immunoglobulin (Ig) loci. Together, our results suggest that bi-directionally transcribed RNA traps the RNA binding protein ROD1, which serves as a guiding system for AID to load onto specific genomic loci to induce DNA rearrangement during immune responses.
2018-08-26 | GSE94662 | GEO