Attracting AID to targets of somatic hypermutation

Tanaka, Atsushi; Sui, Hong; Ratnam, Sarayu; Kodgire, Prashant; Storb, Ursula

doi:10.1084/jem.20090821

Cited by 52 publications

(45 citation statements)

References 49 publications

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“…Recent studies discovered novel cis-acting elements in the IgL locus of the DT40 chicken B cell line that are both essential and sufficient for AIDmediated sequence diversification (59,60). In addition, it was shown that CAGGTG cis elements in the context of Ig enhancers were sufficient and essential to target mutations to a nearby transcribed gene in transgenic DT40 cell lines (61). Overall, these studies highlight an important role of cis regulatory elements in AID targeting to Ig loci (57).…”

Section: Discussionmentioning

confidence: 99%

Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

Chen

Viboolsittiseri

O’Connor

et al. 2012

The Journal of Immunology

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Activation-induced deaminase (AID) catalyses class switch recombination (CSR) and somatic hypermutation (SHM) in B lymphocytes to enhance Ab diversity. CSR involves breaking and rejoining highly repetitive switch (S) regions in the IgH (Igh) locus. S regions appear to be preferential targets of AID. To determine whether S region sequence per se, independent of Igh cis regulatory elements, can influence AID targeting efficiency and mutation frequency, we established a knock-in mouse model by inserting a core Sγ1 region into the first intron of proto-oncogene Bcl6, which is a non-Ig target of SHM. We found that the mutation frequency of the inserted Sγ1 region was dramatically higher than that of the adjacent Bcl6 endogenous sequence. Mechanistically, S region-enhanced SHM was associated with increased recruitment of AID and RNA polymerase II, together with Spt5, albeit to a lesser extent. Our studies demonstrate that target DNA sequences influence mutation frequency via regulating AID recruitment. We propose that the nucleotide sequence preference may serve as an additional layer of AID regulation by restricting its mutagenic activity to specific sequences despite the observation that AID has the potential to access the genome widely.

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Section: Discussionmentioning

confidence: 99%

Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

Chen

Viboolsittiseri

O’Connor

et al. 2012

The Journal of Immunology

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“…It is not entirely clear how AICDA is recruited to gene regulatory regions, although recruitment by the bHLH transcription factor TCF3 E2A is implicated in this process and enrichment in E-box binding sites in GC B-cell hypomethylated genes is consistent with involvement by this factor. 38,42 AICDA was also shown to be recruited to stalled RNA polymerase II in association with replication protein A (RPA 5 ). Collectively, the data suggest that AICDA contributes to epigenetic programming of the GC B cell by either directly or indirectly mediating CpG demethylation, a notion that warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation

Shaknovich¹,

Cerchietti²,

Tsikitas³

et al. 2011

Blood

127

131

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IntroductionOn T-cell dependent activation, resting/naive B cells (NBCs) can be induced to migrate into lymphoid follicles and form germinal centers (GCs). 1,2 GC B cells subsequently undergo massive clonal expansion and mutagenesis mediated by activation-induced cytosine deaminase (AICDA). 2 Tolerance of simultaneous proliferation and genomic instability is a hallmark of the GC B-cell phenotype and is required for development of B-cell clones able to generate high-affinity antibodies. 1,2 AICDA not only induces mutations within the immunoglobulin loci but also localizes to many other sites of the genome including promoters and coding sequences of actively transcribed genes enriched in RGYW DNA motifs. [3][4][5][6] AICDA-induced mutations can thus occur at many sites throughout the genome in normal GCs. 3,6 In accordance with these observations, AICDA has been demonstrated to play a critical role in lymphomagenesis. 7 While genetic diversity of B-cell clones within GCs is important for the emergence of cells encoding high-affinity immunoglobulins, it also provides opportunities for the emergence of malignant clones. In fact a majority of B-cell neoplasms originate from cells that have transited the GC reaction. 1 Induction of the GC phenotype requires that NBCs undergo major changes in gene expression patterning, the basis of which are not fully understood. These shifts are mediated in part by transcription factors such as BCL6 and BACH2 [8][9][10] and histone modifying enzymes such as EZH2. 11 However, differential methylation of CpG dinucleotides is also known to control tissue specific gene expression. 12,13 CpG methylation is mediated by a family of DNA methyltransferase enzymes (DNMTs). 14 Of these, DNMT1 primarily mediates maintenance methylation, because of its preference for hemimethylated DNA 15 ; while DNMT3A and 3B primarily mediate de novo DNA methylation. Differential methylation occurs at the earliest stages of lymphopoiesis 16 and Dnmt1 hypomorphic mice accordingly display skewed hematopoietic differentiation toward the myeloid lineage, 17 but the role of DNMT1 in mature B cells has not been studied in a detailed manner.Both aberrant DNA hypermethylation and hypomethylation have been shown to occur in lymphomas derived from GC B-cells such as diffuse large B-cell lymphomas (DLBCL). 18,19 Furthermore, DLBCLs with GCB (Germinal Center B-cell like) versus ABC (Activated B cell-like) gene expression signatures display distinct DNA methylation profiles, 18 suggesting that cytosine methylation may contribute to the distinct phenotypes of these tumors. Very little is known regarding mechanisms of DNA demethylation, but reports have suggested that cytosine deamination mediated by AICDA followed by base excision The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use onl...

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“…Two copies of the E2A recognition motif was sufficient to enhance SHM of an artificial hypermutable insert within an Igk transgene without affecting the expression of the transgene [53]. Later, it was shown that an artificial GFP-expressing transgene containing just three E2A binding motifs in the context of both Igk enhancers acquired a spectrum of mutations [52]. Furthermore, it was noted that non-Ig genes mistargeted by AID tend to be linked to cis-regulatory elements that contain E-box sites.…”

Section: Aid Targetingmentioning

confidence: 99%

AID targeting: old mysteries and new challenges

Chandra

Bortnick

Murre

2015

Trends in Immunology

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Activation-induced cytidine deaminase (AID) mediates cytosine deamination and underlies two central processes in antibody diversification: somatic hypermutation and class-switch recombination. AID deamination is not exclusive to immunoglobulin loci; it can instigate DNA lesions in non-immunoglobulin genes and thus, stringent checks are in place to constrain and restrict its activity. Recent findings have provided new insights into the mechanisms that target AID activity to specific genomic regions, revealing an involvement for non-coding RNAs associated with polymerase pausing and with enhancer transcription as well as genomic architecture. We review these findings and integrate them into a model for multi-level regulation of AID expression and targeting in immunoglobulin and non-immunoglobulin loci. Within this framework we discuss gaps in understanding, and outline important areas of further research.

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Attracting AID to targets of somatic hypermutation

Cited by 52 publications

References 49 publications

Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation

AID targeting: old mysteries and new challenges

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