Choreography of Ig allelic exclusion

Cedar, Howard; Bergman, Yehudit

doi:10.1016/j.coi.2008.02.002

Cited by 58 publications

(61 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, at the human and murine IgH loci, joining of D to J segments precedes V to DJ joining, and IgH joining precedes joining at Igκ (or Igλ) (3). In addition, recombination at several loci shows "allelic exclusion": Functional VDJH or VJκ/Jλ joining occurs only on one allele (4).…”

mentioning

confidence: 99%

Regulated large-scale nucleosome density patterns and precise nucleosome positioning correlate with V(D)J recombination

Pulivarthy

Lion

Kuzu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We show that the physical distribution of nucleosomes at antigen receptor loci is subject to regulated cell type-specific and lineagespecific positioning and correlates with the accessibility of these gene segments to recombination. At the Ig heavy chain locus (IgH), a nucleosome in pro-B cells is generally positioned over each IgH variable (VH) coding segment, directly adjacent to the recombination signal sequence (RSS), placing the RSS in a position accessible to the recombination activating gene (RAG) recombinase. These changes result in establishment of a specific chromatin organization at the RSS that facilitates accessibility of the genomic DNA for the RAG recombinase. In contrast, in mouse embryonic fibroblasts the coding segment is depleted of nucleosomes, which instead cover the RSS, thereby rendering it inaccessible. Pro-T cells exhibit a pattern intermediate between pro-B cells and mouse embryonic fibroblasts. We also find large-scale variations of nucleosome density over hundreds of kilobases, delineating chromosomal domains within IgH, in a cell typedependent manner. These findings suggest that developmentally regulated changes in nucleosome location and occupancy, in addition to the known chromatin modifications, play a fundamental role in regulating V(D)J recombination. Nucleosome positioning-which has previously been observed to vary locally at individual enhancers and promoters-may be a more general mechanism by which cells can regulate the accessibility of the genome during development, at scales ranging from several hundred base pairs to many kilobases.T he diverse repertoire of antigen receptors in vertebrates is generated by an ordered series of somatic site-specific DNA rearrangement events, collectively termed V(D)J recombination. Antigen receptor genes are assembled from V, D, and J gene segments organized into seven different loci [T-cell receptor (TCR) α, β, γ, and δ, and Ig H, κ, and λ], each of which undergoes a series of recombination reactions to generate a functional TCR or B-cell receptor (BCR) (1, 2) Rearrangement is lineage-specific, such that BCR genes are fully rearranged only in B cells and TCR genes are assembled only in T cells. Rearrangement also occurs in a preferred temporal order. For example, at the human and murine IgH loci, joining of D to J segments precedes V to DJ joining, and IgH joining precedes joining at Igκ (or Igλ) (3). In addition, recombination at several loci shows "allelic exclusion": Functional VDJH or VJκ/Jλ joining occurs only on one allele (4).Recombination is initiated by the lymphocyte-specific recombination activating gene (RAG)1/RAG2 endonuclease. RAG1/2 cleaves at the recombination signal sequences (RSSs) flanking all antigen receptor gene segments. The consensus RSS consists of a heptamer sequence directly adjacent to the coding element and an A/T-rich nonamer separated from the heptamer by a spacer region of conserved length (12 or 23 bp) but relatively nonconserved sequence. The broken ends are then joined with the aid of DNA repair proteins,...

show abstract

mentioning

confidence: 99%

Regulated large-scale nucleosome density patterns and precise nucleosome positioning correlate with V(D)J recombination

Pulivarthy

Lion

Kuzu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Experimentally, approximately 60% of mature T lymphocytes are of the VDJ ϩ /DJ genotype, while 40% are of the VDJ Ϫ /VDJ ϩ genotype (2,(24)(25)(26). The molecular mechanisms responsible for allelic exclusion remain largely unresolved (1,2), and a deficiency in the process of allelic exclusion maintenance results in the generation of cells that express two functional TCRs, which can lead to autoimmunity (27,28).…”

mentioning

confidence: 99%

“…O ne enduring mystery in cellular immunology regards the underlying mechanisms that control antigen receptor allelic exclusion (1,2), the process whereby B or T lymphocytes are programmed to express only one functional allele for each chain of their respective antigen receptors (B cell receptor [BCR] or T cell receptor [TCR]), thus avoiding the coexistence of multiple antigen specificities in a single immune cell. Lymphocytes acquire the diversity of antigen recognition (3) as well as a unique monospecificity for particular antigens (4) during development in the bone marrow (B cells) or the thymus (T cells).…”

mentioning

confidence: 99%

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Sekiguchi

Panwar

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

Allelic exclusion describes the essential immunological process by which feedback repression of sequential DNA rearrangements ensures that only one autosome expresses a functional T or B cell receptor. In wild-type mammals, approximately 60% of cells have recombined the DNA of one T cell receptor ␤ (TCR␤) V-to-DJ-joined allele in a functional configuration, while the second allele has recombined only the DJ sequences; the other 40% of cells have recombined the V to the DJ segments on both alleles, with only one of the two alleles predicting a functional TCR␤ protein. Here we report that the transgenic overexpression of GATA3 leads predominantly to biallelic TCR␤ gene (Tcrb) recombination. We also found that wild-type immature thymocytes can be separated into distinct populations based on intracellular GATA3 expression and that GATA3 LO cells had almost exclusively recombined only one Tcrb locus (that predicted a functional receptor sequence), while GATA3 HI cells had uniformly recombined both Tcrb alleles (one predicting a functional and the other predicting a nonfunctional rearrangement). These data show that GATA3 abundance regulates the recombination propensity at the Tcrb locus and provide new mechanistic insight into the historic immunological conundrum for how Tcrb allelic exclusion is mediated.KEYWORDS allelic exclusion, T cell receptor beta locus, GATA3, monoallelic-tobiallelic switch O ne enduring mystery in cellular immunology regards the underlying mechanisms that control antigen receptor allelic exclusion (1, 2), the process whereby B or T lymphocytes are programmed to express only one functional allele for each chain of their respective antigen receptors (B cell receptor [BCR] or T cell receptor [TCR]), thus avoiding the coexistence of multiple antigen specificities in a single immune cell. Lymphocytes acquire the diversity of antigen recognition (3) as well as a unique monospecificity for particular antigens (4) during development in the bone marrow (B cells) or the thymus (T cells).T lymphocyte development is generally characterized by division into multiple stages based on developmental timing and the location and expression of specific cell surface markers (5). T cell development begins when multipotential hematopoietic progenitor cells in the bone marrow migrate through the bloodstream to the thymus, where early T lineage progenitors (ETPs) are generated and later specified to become T cells (6-10). ETPs differentiate into double-negative (DN) cells (DN2 to DN4 stages) that express neither the CD4 nor the CD8 coreceptor, then into double-positive (DP)

show abstract

“…Multiple mechanisms most likely contribute to allelic exclusion, but the relative role of the proposed models remains controversial (15)(16)(17). The allelic-exclusion system ensures that successful V(D)J recombination on one allele shuts off recombination on the other allele by feedback inhibition to prevent a second successful rearrangement (15)(16)(17). This feedback inhibition from AgRs has an established major role in allelic exclusion, but little is known about the molecular mechanism(s) by which it is achieved (15)(16)(17).…”

mentioning

confidence: 99%

“…This allelic exclusion requires that only one allele at a time undergoes complete V(D)J recombination. Multiple mechanisms most likely contribute to allelic exclusion, but the relative role of the proposed models remains controversial (15)(16)(17). The allelic-exclusion system ensures that successful V(D)J recombination on one allele shuts off recombination on the other allele by feedback inhibition to prevent a second successful rearrangement (15)(16)(17).…”

mentioning

confidence: 99%

Allelic Exclusion of IgH through Inhibition of E2A in a VDJ Recombination Complex

Hauser

Grundström

2014

The Journal of Immunology

View full text Add to dashboard Cite

A key feature of the immune system is the paradigm that one lymphocyte has only one Ag specificity that can be selected for or against. This requires that only one of the alleles of genes for AgR chains is made functional. However, the molecular mechanism of this allelic exclusion has been an enigma. In this study, we show that B lymphocytes with E2A that cannot be inhibited by calmodulin are dramatically defective in allelic exclusion of the IgH locus. Furthermore, we provide data supporting that E2A, PAX5, and the RAGs are in a VDJ recombination complex bound to key sequences on the Igh gene. We show that pre-BCR activation releases the VDJ recombination complex through calmodulin binding to E2A. We also show that pre-BCR signaling downregulates several components of the recombination machinery, including RAG1, RAG2, and PAX5, through calmodulin inhibition of E2A.

show abstract

Choreography of Ig allelic exclusion

Cited by 58 publications

References 74 publications

Regulated large-scale nucleosome density patterns and precise nucleosome positioning correlate with V(D)J recombination

Regulated large-scale nucleosome density patterns and precise nucleosome positioning correlate with V(D)J recombination

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Allelic Exclusion of IgH through Inhibition of E2A in a VDJ Recombination Complex

Contact Info

Product

Resources

About