Pax5 inducesV-to-DJrearrangements and locus contraction of theimmunoglobulin heavy-chaingene

Fuxa, Martin; Skok, Jane A.; Souabni, Abdallah; Salvagiotto, Giorgia; Roldán, Esther; Busslinger, Meinrad

doi:10.1101/gad.291504

Cited by 378 publications

(488 citation statements)

References 59 publications

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“…Long-range recombination of V gene segments at all Ig and Tcr loci is facilitated by a contraction process, which places the V cluster into spatial proximity with distal (D)J targets located 0.1-3.2 Mb away in the linear genome (3,25). Deletion of transcription factors or cis elements that disrupt locus contraction significantly impair V to (D)J recombination, supporting a functional link between these processes (13,(26)(27)(28). Additional evidence indicates that V clusters fold into a compact rosettelike structure, which may permit extensive interactions between a recombination center and many or all of its upstream V segments (14).…”

Section: Spatial Access Of Vβ Gene Segments To the Dβjβ Recombinationmentioning

confidence: 99%

Unifying model for molecular determinants of the preselection Vβ repertoire

Gopalakrishnan

Majumder

Predeus

et al. 2013

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

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The primary antigen receptor repertoire is sculpted by the process of V(D)J recombination, which must strike a balance between diversification and favoring gene segments with specialized functions. The precise determinants of how often gene segments are chosen to complete variable region coding exons remain elusive. We quantified Vβ use in the preselection Tcrb repertoire and report relative contributions of 13 distinct features that may shape their recombination efficiencies, including transcription, chromatin environment, spatial proximity to their DβJβ targets, and predicted quality of recombination signal sequences (RSSs). We show that, in contrast to functional Vβ gene segments, all pseudo-Vβ segments are sequestered in transcriptionally silent chromatin, which effectively suppresses wasteful recombination. Importantly, computational analyses provide a unifying model, revealing a minimum set of five parameters that are predictive of Vβ use, dominated by chromatin modifications associated with transcription, but largely independent of precise spatial proximity to DβJβ clusters. This learned model-building strategy may be useful in predicting the relative contributions of epigenetic, spatial, and RSS features in shaping preselection V repertoires at other antigen receptor loci. Ultimately, such models may also predict how designed or naturally occurring alterations of these loci perturb the preselection use of variable gene segments.lymphocytes | T-cell receptor | gene regulation G ene activity is regulated at multiple levels to coordinate expression during development. At a most basic level, the collection of cis-acting elements for a genetic locus recruits transcription factors that alter its chromatin environment to either induce or repress gene activity. Emerging studies indicate that the 3D conformation of a locus also plays an important role in the regulation of its composite genes (1). At most genes, many levels of control are integrated to achieve the requisite gene expression state. For example, transcriptional promoters interact with their cognate enhancers over considerable distances in the linear genome to generate "hubs" where the two cis elements are in spatial proximity (1, 2).All of these regulatory strategies are used to generate functional Ig (Ig) and T-cell receptor (Tcr) genes during lymphocyte development (3). Each antigen receptor (AgR) locus is composed of multiple variable (V), joining (J), and sometimes diversity (D) gene segments that are assembled by the process of V (D)J recombination, creating a potential variable region exon (4). Recombination is mediated by the RAG-1/2 enzymatic complex, which is expressed in all developing lymphocytes and recognizes semiconserved recombination signal sequences (RSSs) flanking all AgR gene segments (5). On selection of two compatible gene segments by RAG-1/2, recombination proceeds via a DNA break/repair mechanism, ultimately fusing the two selected segments (4, 5).The assembly of AgR genes is strictly regulated despite a common collection of ge...

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Section: Spatial Access Of Vβ Gene Segments To the Dβjβ Recombinationmentioning

confidence: 99%

Unifying model for molecular determinants of the preselection Vβ repertoire

Gopalakrishnan

Majumder

Predeus

et al. 2013

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

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“…In pro-B nuclei, the IgH locus is centrally located and undergoes large-scale compaction. This compacted state facilitates long-range V-to-DJ rearrangements, particularly of the distal V H J558 genes (Kosak et al, 2002), and it is mediated by the transcription factor Pax5 (Fuxa et al, 2004). In thymocytes, however, the inactive IgH locus is mainly localized at the nuclear periphery through an interaction with the nuclear lamina or its associated proteins, but not with centromeric heterochromatin (Kosak et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…DJ H -distal V H gene segments are blocked from undergoing V H -to-DJ H rearrangement in pro-B cells from Pax5-deficient mice (Urbanek et al, 1994;Nutt et al, 1997;Hesslein et al, 2003). Until recently, there was evidence for two roles of Pax5 in controlling V H -to-DJ H rearrangements: (a) facilitating rearrangement of distal V H genes by inducing IgH locus contraction (Fuxa et al, 2004), and (b) removing histone H3 methylated at lysine 9, a marker of repressed chromatin, from the V H locus, making V H genes accessible for V H -to DJ H recombination (Johnson et al, 2004). In addition, we recently reported that Pax5 binds to V H coding regions and to the RAG1/ RAG2 complex, which may facilitate RAG mediated recombination of individual V H genes (Zhang et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Chromatin accessibility and epigenetic modifications differ between frequently and infrequently rearranging VH genes

Espinoza

Feeney

2007

Molecular Immunology

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The molecular mechanisms that control the temporal and lineage-specific accessibility, as well as the rearrangement frequency of V H genes for V H -to-DJ H recombination, are not fully understood. We previously found a positive correlation between the extent of histone acetylation and the differential rearrangement frequency of individual V H genes. Here, we demonstrated that poorly rearranging V H genes are more highly associated with histone H3 dimethylated at lysine 9, a marker of repressive chromatin, than frequently rearranging V H genes. We also observed a positive relationship between the differential binding of Pax5 to individual V H S107 genes and rearrangement frequency. Furthermore, we showed that accessibility of the regions flanking the Pax5 binding site and the RSS to restriction enzyme cleavage correspond with the differential rearrangement frequency of the V H S107 family members. In addition, we found that the CpG sites located in the coding regions of V H genes are methylated in general, while the extent of DNA methylation drops dramatically near the RSS. For the V H S107 family, one CpG site located 101 bp upstream of the RSS showed variable methylation that correlates with rearrangement frequency, and the methylation status of a CpG site located 34 bp downstream of the RSS could also favor the rearrangement of V1 over V11. These findings suggest that the extent of histone modifications, chromatin accessibility, DNA methylation, as well as the differential binding of Pax5 to V H coding regions, could all influence the rearrangement frequency of individual V H genes, although some of these mechanisms are not strictly B cell specific.

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“…Progress has been slow, but a recent report that certain mouse V H clusters have PAX5 target elements harboring intrinsic enhancer activity may provide a much-needed boost (27). Beyond chromatin accessibility, it is now clear that the three-dimensional structure of AgR loci plays an important role in facilitating long-range recombination, including V to DJ H (28,29). However, the cause-effect relationships, if any, among chromatin accessibility, transcription, and changes in locus topology remain key questions for the future.…”

Section: Preparing Targets For V(d)j Recombinase: Transcription Pavesmentioning

confidence: 99%

Preparing Targets for V(D)J Recombinase: Transcription Paves the Way

Sleckman

Oltz

2012

The Journal of Immunology

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Pax5 inducesV-to-DJrearrangements and locus contraction of theimmunoglobulin heavy-chaingene

Abstract: Cold Spring Harbor Laboratory Press on May 11, 2018 -Published by genesdev.cshlp.org Downloaded from

Cited by 378 publications

References 59 publications

Unifying model for molecular determinants of the preselection Vβ repertoire

Unifying model for molecular determinants of the preselection Vβ repertoire

Chromatin accessibility and epigenetic modifications differ between frequently and infrequently rearranging VH genes

Preparing Targets for V(D)J Recombinase: Transcription Paves the Way

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