Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus.

Chen, Jianzhu; Young, Faith; Bottaro, Andrea; Stewart, Victoria; Smith, Ryan J.; Alt, Frederick W.

doi:10.1002/j.1460-2075.1993.tb06152.x

Cited by 175 publications

(137 citation statements)

References 45 publications

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“…Transcriptional activation may therefore target immunoglobulin genes for V(D)J recombination. In agreement with this hypoth esis, V(D)J recombination is impaired by germ-line dele tion of the intronic enhancers of the IgH locus (Chen et al 1993;Serwe and SabUtzky 1993) and IgU gene (Takeda et al 1993) or by the lack of the Ep enhancer on transgenic recombination substrates (Ferrier et al 1990). As both intronic enhancers do not contain any high-af finity binding sites for BSAP (Barberis et al 1990), it is unlikely that Pax5 mediates its effect on V(D)J recombi nation by direct interaction with these regulatory re gions.…”

Section: Paxs and The B-cell-specific Control Of V(d)j Recombinationmentioning

confidence: 70%

Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus.

Nutt¹,

Urbánek²,

Rolink³

et al. 1997

Genes Dev.

379

377

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Section: Paxs and The B-cell-specific Control Of V(d)j Recombinationmentioning

confidence: 70%

Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus.

Nutt¹,

Urbánek²,

Rolink³

et al. 1997

Genes Dev.

379

377

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“…Some substrates did have discordant effects on these properties; whereas some substrates were transcriptionally active but recombinationally silent (34,35), others were transcriptionally silent but recombinationally active (36). Additionally, a genetically modified heavy chain locus was developmentally demethylated but recombinationally silent (37). Therefore, transcription and demethylation per se are not simply permissive for rearrangement, but specific enhancer sequences and cognate binding factors must be critical.…”

Section: Discussionmentioning

confidence: 99%

“…This supports our findings at the kappa locus. Moreover, recent studies using an episomal recombination substrate demonstrated that the repression of recombination by methylation could be overcome, at least in part, by changes in chromatin structure, suggesting a role for specific factors in remodeling chromatin for recombination (37).…”

Section: Discussionmentioning

confidence: 99%

V(D)J recombination is not activated by demethylation of the kappa locus

Cherry

Beard

Jaenisch

et al. 2000

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

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V(D)J recombination is thought to be regulated by changes in the accessibility of target sites, such as modulation of methylation. To test whether demethylation of the kappa locus can activate recombination, we generated two recombinationally active B cell lines in which the gene for maintenance of genomic DNA methylation, Dnmt1, was flanked with loxP sites. Transduction with a retrovirus expressing both the cre recombinase and green fluorescent protein allowed us to purify recombinationally active cells devoid of methylation. Loss of methylation of the kappa locus was not sufficient to activate recombination, although transcription was activated in one line. It appears that demethylation of the kappa locus is not the rate-limiting step for altering accessibility and thus regulated demethylation does not generate specificity of recombination.T he V(D)J recombination machinery assembles antigen receptor genes during lymphoid development from gene segments flanked by recombination signal sequences (1). This nonhomologous site-specific recombination process is precisely controlled by a number of different regulatory mechanisms. For one thing, the coexpression of the lymphoid-specific Rag-1 and Rag-2 genes occurs restrictively in developing B and T cells, ensuring that only the appropriate cell types are recombinationally active (2). A second level of regulation also controls lineage specificity: complete Ig gene rearrangement occurs only in B cells, whereas T cell receptor genes rearrange exclusively in T cells (3). Moreover, within developing B and T cells there are temporal controls over specific gene segment usage (4, 5). Additionally, allelic exclusion ensures that each B or T cell generates only one functional antigen receptor even though two alleles exist at each locus (6).This remarkable ability of the recombination machinery to target only a very small subset of substrates within a given cell together with the fact that a single recombinase is required for this process has led to the hypothesis that the accessibility of DNA targets to the recombination machinery is tightly controlled (7-9). Recombination loci are thought to be inaccessible until they are modified to allow the recombination machinery access to target sites. Changes in chromatin structure, transcriptional activity, or DNA methylation at each locus have been identified that correlate with recombinational activity. Many studies have attempted to define the cis-acting sequences and trans-acting factors required to regulate this process. Distinct enhancer sequences present within individual loci must be controlled by different trans-acting proteins to allow developmentally regulated changes in the accessibility of each locus to occur.DNA methylation has been shown to regulate chromatin structure, leading to changes of gene expression (10). Additionally, methylation has been correlated with Ig gene regulation: both the heavy chain and light chain are hypermethylated in cells in which they are not recombined (11,12). Concomitant with V(D)J rearrang...

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“…1). The first of these, E , is found in an intron separating the V region and C region coding sequences and, although initially discovered because of its ability to enhance transcription from the promoter of an assembled IgH gene, it has since been shown to be essential for efficient V-D-J recombination (3)(4)(5)(6)(7)(8)(9). The other four enhancers lie at the far 3Ј end of the IgH locus and have been shown to contribute substantially to IgH gene transcription in Ig-secreting cells as well as play an important role in CSR (10,11).…”

Section: Transcription Of a Productively Rearranged Ig Vdjc␣ Does Notmentioning

confidence: 99%

Transcription of a Productively Rearranged Ig VDJCα Does Not Require the Presence of HS4 in the Igh 3′ Regulatory Region

Zhang

Alaie-Petrillo

Kon

et al. 2007

The Journal of Immunology

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V gene assembly, class switch recombination, and somatic hypermutation are gene-modifying processes essential to the development of an effective Ab response. If inappropriately applied, however, these processes can mediate genetic changes that lead to disease (e.g., lymphoma). A series of control elements within the Ig H chain (Igh) locus has been implicated in regulating these processes as well as in regulating IgH gene transcription. These include the intronic enhancer (Eμ) and several elements at the 3′ end of the locus (hs1,2, hs3a, hs3b, and hs4) known collectively as the 3′ regulatory region. Although it is clear that the Eμ plays a unique role in V gene assembly, it has not been established whether there are unique functions for each element within the 3′ regulatory region. In earlier studies in mice and in mouse cell lines, pairwise deletion of hs3b and hs4 had a dramatic effect on both class switch recombination and IgH gene transcription; deletion of an element almost identical with hs3b (hs3a), however, yielded no discernible phenotype. To test the resulting hypothesis that hs4 is uniquely required for these processes, we induced the deletion of hs4 within a bacterial artificial chromosome transgene designed to closely approximate the 3′ end of the natural Igh locus. When introduced into an Ig-secreting cell line, an Igα transcription unit within the bacterial artificial chromosome was expressed efficiently and the subsequent deletion of hs4 only moderately affected Igα expression. Thus, hs4 does not play a uniquely essential role in the transcription of a productively rearranged Ig VDJCα transcription unit.

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Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus.

Cited by 175 publications

References 45 publications

Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus.

Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus.

V(D)J recombination is not activated by demethylation of the kappa locus

Transcription of a Productively Rearranged Ig VDJCα Does Not Require the Presence of HS4 in the Igh 3′ Regulatory Region

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