Allelic 'choice' governs somatic hypermutation in vivo at the immunoglobulin κ-chain locus

Fraenkel, Shira; Mostoslavsky, Raúl; Novobrantseva, Tatiana; Pelanda, Roberta; Chaudhuri, Jayanta; Esposito, Gloria; Jung, Steffen; Alt, Frederick W.; Rajewsky, Klaus; Cedar, Howard; Bergman, Yehudit

doi:10.1038/ni1476

Cited by 44 publications

(37 citation statements)

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“…Multiple lines of evidence have linked the generation of ssDNA and the recruitment of AID to the level of transcription (Peters & Storb, 1996; Fukita et al , 1998; Ramiro et al , 2003). AID activity at the IgV genes is thus associated with chromatin features characteristic of actively transcribed loci including DNA hypomethylation, enrichment for the histone modifications H3K4me3 and H3K36me3 and the variant histone H3.3 (Fraenkel et al , 2007; Begum et al , 2012; Aida et al , 2013). However, whether any of these features promotes the activity of AID directly, that is independently of simply promoting transcription, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

et al. 2016

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Immunoglobulin diversification is driven by activation‐induced deaminase (AID), which converts cytidine to uracil within the Ig variable (IgV) regions. Central to the recruitment of AID to the IgV genes are factors that regulate the generation of single‐stranded DNA (ssDNA), the enzymatic substrate of AID. Here, we report that chicken DT40 cells lacking variant histone H3.3 exhibit reduced IgV sequence diversification. We show that this results from impairment of the ability of AID to access the IgV genes due to reduced formation of ssDNA during IgV transcription. Loss of H3.3 also diminishes IgV R‐loop formation. However, reducing IgV R‐loops by RNase HI overexpression in wild‐type cells does not affect IgV diversification, showing that these structures are not necessary intermediates for AID access. Importantly, the reduction in the formation of AID‐accessible ssDNA in cells lacking H3.3 is independent of any effect on the level of transcription or the kinetics of RNAPII elongation, suggesting the presence of H3.3 in the nucleosomes of the IgV genes increases the chances of the IgV DNA becoming single‐stranded, thereby creating an effective AID substrate.

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Section: Introductionmentioning

confidence: 99%

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

et al. 2016

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“…compu-tational predictions based on DNA sequence characteristics or detection of monoallelic expression) of some regions with monoallelic DNA-methylation (2,3,(10)(11)(12)(13)(14)(15)(16), only a few imprinted regions are well characterized in humans, like, for example, the IGF2/H19 region. Furthermore, monoallelic methylation has recently been recognized as very common at non-imprinted loci affecting autosomal genes, regulating, for example, the production of specific antibodies and receptors in the immune system as well as the selection of olfactory receptors (17,18). While monoallelic methylation has been shown to play an important role in the differentiation between tissues, little is known about the specific location of these loci as well as the genome-wide character of monoallelic DNA-methylation.…”

Section: Introductionmentioning

confidence: 99%

SNP-guided identification of monoallelic DNA-methylation events from enrichment-based sequencing data

Steyaert¹,

Criekinge²,

Paepe³

et al. 2014

Preprint

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“…During B-lineage development, demethylation occurs in a monoallelic fashion prior to the onset of IgK VJ gene rearrangement [34]. Interestingly, recent studies have indicated that the demethylated IgK allele is also selectively targeted by AID [35].…”

Section: Developmental-specific Regulation Of Antigen Receptor Gene Amentioning

confidence: 99%

Epigenetics of antigen-receptor gene assembly

Murre

2007

Current Opinion in Genetics & Development

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IntroductionIt is established that the temporal and lineage specificity of V(D)J rearrangement is controlled at multiple levels [1,2]. These include germ-line transcription, chromatin remodeling, histone acetylation and DNA methylation. It is, however, unknown how a region spanning large genomic distances allows the assembly of antigen receptor genes. Recent data have suggested that an underlying structural order must exist that facilitates the association of DNA elements separated by large genomic distances. B cell development and ordered immunoglobulin gene rearrangementThe developmental progression of B cells has been characterized on the basis of antigen receptor gene rearrangements and on the dynamic expression patterns of cell surface proteins, which have served as maturation markers [3]. The Igh locus is comprised of distinct DNA elements encoding the variable (V), diversity (D), joining (J), and constant (C) regions. Eight Igh constant regions encode for distinct isotypes that include C μ , C δ , C γ1 C γ2a , C γ2b , C γ3 , C α and C ε . Upstream of the IgM constant region are located twelve D H and four J H segments. Fifteen partially dispersed V region families are present that span approximately 2 Mbp of genomic sequence. The IgK and L light chain loci are also organized into distinct DNA elements, encoding V H , J H and C H segments. Ig V H , D H and J H elements are flanked by recombination signal sequences that interact with the RAG1 and RAG2 gene products.In pro-B cells, Igh D H J H joining precedes that of V H (D H )J H gene rearrangement [4]. Once a V(D)J gene rearrangement leads to a productive joint, pre-BCR signaling acts to inhibit RAG1 and RAG2 gene expression and to promote the survival, expansion and developmental progression of large pre-B cells [5.6]. The expansion phase is followed by cell cycle arrest, during which RAG gene expression is reactivated to initiate the rearrangement of the Ig light chain genes. In the presence of self-reactivity, continued rearrangements will replace primary IgK VJ joints, generating receptors with novel specificities. Once a BCR is expressed which lacks auto-reactivity, tonic signaling mediated by the BCR will permanently suppress RAG1 and RAG2 gene expression. Tonic BCR signaling will also trigger the migration of B cells to the peripheral lymphoid organs where they, upon interacting with pathogens, will undergo class switching and somatic hypermutation. T-lineage development and T cell receptor gene rearrangementT-lineage cells also develop sequentially [7]. Two distinct T cell lineages develop from a common progenitor, named αβ and γδ T cells. The rearrangement of the TCRβ and γδ loci is Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production...

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Allelic 'choice' governs somatic hypermutation in vivo at the immunoglobulin κ-chain locus

Cited by 44 publications

References 48 publications

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

SNP-guided identification of monoallelic DNA-methylation events from enrichment-based sequencing data

Epigenetics of antigen-receptor gene assembly

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