Chromatin Architecture and the Generation of Antigen Receptor Diversity

Jhunjhunwala, Suchit; Zelm, Menno C. van; Peak, Mandy M.; Murre, Cornelis

doi:10.1016/s9999-9994(09)20447-8

Cited by 33 publications

(54 citation statements)

References 49 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conformational changes of antigen receptor loci are believed to support V(D)J recombination events because they can bring distant RSSs into proximity and therefore increase the probability of RSS synapsis (2,3). Studies using 3D-FISH have demonstrated that lineage-and development stage-specific locus contraction marks the recombination windows at antigen receptor loci (3).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Tcragene recombination is supported by aTcraenhancer- and CTCF-dependent chromatin hub

Shih

Verma-Gaur

Torkamani

et al. 2012

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

153

View full text Add to dashboard Cite

Antigen receptor locus V(D)J recombination requires interactions between widely separated variable (V), diversity (D), and joining (J) gene segments, but the mechanisms that generate these interactions are not well understood. Here we assessed mechanisms that direct developmental stage-specific long-distance interactions at the Tcra/Tcrd locus. The Tcra/Tcrd locus recombines Tcrd gene segments in CD4 − CD8 − double-negative thymocytes and Tcra gene segments in CD4 + CD8 + double-positive thymocytes. Initial V α -to-J α recombination occurs within a chromosomal domain that displays a contracted conformation in both thymocyte subsets. We used chromosome conformation capture to demonstrate that the Tcra enhancer (E α ) interacts directly with V α and J α gene segments distributed across this domain, specifically in double-positive thymocytes. Moreover, E α promotes interactions between these V α and J α segments that should facilitate their synapsis. We found that the CCCTC-binding factor (CTCF) binds to E α and to many locus promoters, biases E α to interact with these promoters, and is required for efficient V α -J α recombination. Our data indicate that E α and CTCF cooperate to create a developmentally regulated chromatin hub that supports V α -J α synapsis and recombination.T-cell development | T-cell receptor | thymus T and B cells produce diverse antigen receptors through the recombination of variable (V), diversity (D), and joining (J) gene segments at the T-cell receptor (Tcra, Tcrb, Tcrg, and Tcrd) and Ig (Igh, Igκ, and Igλ) loci. This V(D)J recombination is initiated by the lymphoid-specific recombination-activating gene-1 (RAG-1) and RAG-2 proteins, which recognize the recombination signal sequences (RSSs) that flank all V, D, and J gene segments and then cleave the DNA between the RSSs and the adjacent coding gene segments (1). A critical feature of the reaction is the assembly of a synaptic complex composed of two RSSs before the generation of RAG-dependent DNA doublestrand breaks (DSBs). As such, lineage-and developmental stagespecific V(D)J recombination events can be regulated not only by changes in RAG protein expression and RSS accessibility to RAG proteins but also by the ability of those RSSs to undergo synapsis (2).Conformational changes of antigen receptor loci are believed to support V(D)J recombination events because they can bring distant RSSs into proximity and therefore increase the probability of RSS synapsis (2, 3). Studies using 3D-FISH have demonstrated that lineage-and development stage-specific locus contraction marks the recombination windows at antigen receptor loci (3). For example, the 3-Mb Igh locus contracts specifically in pro-B cells to support V H -to-D H J H recombination (4-7). This contracted conformation brings distal and proximal V H segments, which are separated by megabases in the linear DNA sequence, to the vicinity of the D H J H cluster, presumably allowing all V H segments a similar opportunity for recombination (8). In addition, the mapping of Igh locus DNA-DNA...

show abstract

mentioning

confidence: 99%

“…Studies using 3D-FISH have demonstrated that lineage-and development stage-specific locus contraction marks the recombination windows at antigen receptor loci (3). For example, the 3-Mb Igh locus contracts specifically in pro-B cells to support V H -to-D H J H recombination (4)(5)(6)(7).…”

mentioning

confidence: 99%

Tcragene recombination is supported by aTcraenhancer- and CTCF-dependent chromatin hub

Shih

Verma-Gaur

Torkamani

et al. 2012

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

153

View full text Add to dashboard Cite

show abstract

“…When Igh is accessible to the recombination machinery, chromosomal contraction and DNA looping enable recombination, whereas chromosomal expansion inhibits the recombination (46,47). During VDJ recombination of Igh, the chromatin of the locus is organized in compartments containing clusters of loops separated by linkers, and the entire repertoire of V regions merges and juxtaposes to D elements (48,49). Productive V-DJ recombination at the Igh locus leads to reversal of locus compaction, and this decontraction was postulated to enforce allelic exclusion (47).…”

Section: Discussionmentioning

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

“…The developmental and locus-specific constraints on V(D)J recombination are largely imposed at the epigenetic level (Jhunjhunwala et al 2009). In nonlymphoid cells, the Ig and TCR genes are present in inaccessible chromatin because exogenously expressed RAG proteins readily cleave transfected episomal recombination substrates but not endogenous antigen receptor genes in kidney cells (Romanow et al 2000).…”

Section: Developmental Regulation Of Antigen Receptor Gene Rearrangemmentioning

confidence: 99%

Epigenetic Control of Immunity

Busslinger

Tarakhovsky

2014

Cold Spring Harbor Perspectives in Biology

110

View full text Add to dashboard Cite

SUMMARYImmunity relies on the heterogeneity of immune cells and their ability to respond to pathogen challenges. In the adaptive immune system, lymphocytes display a highly diverse antigen receptor repertoire that matches the vast diversity of pathogens. In the innate immune system, the cell's heterogeneity and phenotypic plasticity enable flexible responses to changes in tissue homeostasis caused by infection or damage. The immune responses are calibrated by the graded activity of immune cells that can vary from yeast-like proliferation to lifetime dormancy. This article describes key epigenetic processes that contribute to the function of immune cells during health and disease.

show abstract

Chromatin Architecture and the Generation of Antigen Receptor Diversity

Cited by 33 publications

References 49 publications

Tcragene recombination is supported by aTcraenhancer- and CTCF-dependent chromatin hub

Tcragene recombination is supported by aTcraenhancer- and CTCF-dependent chromatin hub

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

Epigenetic Control of Immunity

Contact Info

Product

Resources

About