Evidence for Physical Interaction between the Immunoglobulin Heavy Chain Variable Region and the 3′ Regulatory Region

Zhang, Ju; Volpi, Sabrina A.; Hassan, Rabih; Martinez, Nancy E.; Giannini, Sandra L.; Gold, Tamar; Birshtein, Barbara K.

doi:10.1074/jbc.m705719200

Cited by 47 publications

(74 citation statements)

References 36 publications

(45 reference statements)

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“…The major players in such synapses are the 39 LCR, the intronic enhancer Em, and the V H promoter of the rearranged VDJ exon that are found juxtaposed in resting and activated B cells (31,32). Upon activation, donor and acceptor switch regions might be recruited to the former synapse to be transcribed and recombined in a CSR synaptic holocomplex (32).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Redundant Function of the 3′ IgH Regulatory Element HS3b in the Mouse

Bébin

Carrion

Marquet

et al. 2010

The Journal of Immunology

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In the mouse, the regulatory region located at the 3′ end of the IgH locus includes four transcriptional enhancers: HS3a, HS1-2, HS3b, and HS4; the first three lie in a quasi-palindromic structure. Although the upstream elements HS3a and HS1-2 proved dispensable for Ig expression and class switch recombination (CSR), the joint deletion of HS3b and HS4 led to a consistent decrease in IgH expression in resting B cells and to a major CSR defect. Within this pair of distal enhancers, it was questionable whether HS3b and HS4 could be considered individually as elements critical for IgH expression and/or CSR. Studies in HS4-deficient mice recently revealed the role of HS4 as restricted to Igμ-chain expression from the pre-B to the mature B cell stage and left HS3b as the last candidate for CSR regulation. Our present study finally invalidates the hypothesis that CSR could mostly rely on HS3b itself. B cells from HS3b-deficient animals undergo normal proliferation, germline transcription, and CSR upon in vitro stimulation with LPS; in vivo Ag-specific responses are not affected. In conclusion, our study highlights a major effect of the global ambiance of the IgH locus; enhancers demonstrated as being strongly synergistic in transgenes turn out to be redundant in their endogenous context.

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Section: Discussionmentioning

confidence: 99%

In Vivo Redundant Function of the 3′ IgH Regulatory Element HS3b in the Mouse

Bébin

Carrion

Marquet

et al. 2010

The Journal of Immunology

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“…Longrange interactions between the two regions of chromatin, through formation of a loop structure, constitute an important mechanism of normal and abnormal gene transcription regulation by the 3 0 RR. Studies have reported interactions between the 3 0 RR, Em and the IgH variable region in normal and lymphomagenetic contexts [19,20,35,36]. Mouse models for oncogene translocations involving the IgH locus effectively produce an insight into the molecular mechanisms of the translocated oncogene deregulation involved in B-cell malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…If a global IgH transcription defect is observed in activated 3 0 RR-deficient mouse B cells, the persistence of IgM expression and germline transcription suggests that additional elements, such as Em, must cooperate with the 3 0 RR. Chromosome conformation capture experiments suggest the production of unique chromosomal loops in peripheral B cells anchored by Em and 3 0 RR physical interactions [19,20]. In the case of CSR, recruitment and transcription of the switch-acceptor region in close proximity to the switch m donor region (switch--switch synapsis) might be promoted by the 3 0 RR itself [19].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, combined deletion of both hs3b and hs4 affected CSR as a consequence of impairment of the Ig constant gene germline transcription to most isotypes (except g1) [16]. Recently the complete deletion of the 3 0 RR in large [19,20]. In the case of CSR, recruitment and transcription of the switch-acceptor region in close proximity to the switch m donor region (switch--switch synapsis) might be promoted by the 3 0 RR itself [19].…”

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confidence: 99%

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The IgH 3′ regulatory region and its implication in lymphomagenesis

et al. 2010

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The 3 0 regulatory region (3 0 RR) located downstream of the IgH gene is the master element that controls class switch recombination and sustains high-level transcription at the plasma-cell stage. This latter role suggests that the 3 0 RR may be involved in oncogene deregulation during the frequent IgH translocation events associated with B-cell malignancies. A convincing demonstration of the essential contribution of 3 0 RR in lymphomagenesis has been provided by transgenic animal models. The mouse 3 0 RR shares a strong structural homology with the regulatory regions located downstream of each human Ca gene. Mouse models exploring the role of the 3 0 RR in B-cell physiology and in malignancies should provide useful indications about the pathophysiology of human cell lymphocyte proliferation.Key words: B cells . Cellular proliferation . Oncology IntroductionDuring precursor B-cell differentiation, genes encoding heavy (H) and light chains of an Ig molecule are somatically assembled from germline DNA. This process, named V(D)J recombination, occurs in the bone marrow prior to antigenic challenge. In germinal centers during the antigen-dependent stages, variable (V) regions become the target of somatic hypermutation (SHM) in activated B cells allowing the generation of high-affinity Ig. In mature B cells, class switch recombination (CSR) deletes the constant (C) m region and replaces it with a downstream C H gene. This enables B cells to express various Ig isotypes but still retain antigen specificity. Once activated, B cells differentiate into Ig-secreting plasma cells. During B-cell development all these events (V(D)J recombination, SHM, CSR, Ig synthesis) are coupled with transcriptional accessibility of the IgH loci. IgH transcription is controlled by the functional interactions of multiple promoters, enhancers and insulators spread among the 2.5 megabases of the locus. Among them, the upstream Em enhancer and the 3 0 regulatory region (3 0 RR) stand out as major players. Chromosomal translocations linking oncogenes to these elements are often implicated as the cause of B-cell malignancies. In this brief review of relevant knock-out and transgenic mouse models, we underline how the physiological functions of the IgH 3 0 RR might translate into a critical role in oncogene deregulation during lymphomagenesis.From the El cis-activating element to the 3 0 RR Thirty years ago, Em was the first transcriptional enhancer discovered upstream of the m gene (Fig. 1A) [1][2][3]. Em deletion in mice confirmed its role in controlling access to the locus prior to D-J recombination, but, moreover, showed its dispensability for CSR and SHM [4]. Eventually, several more transcriptional enhancers were identified at the 3 0 end of the locus. hs1,2 was identified 12.5-kb downstream of the mouse Ca (Fig. 1A) 3306Mini-Review differentiation stages, while hs4 is active during the pre-B-cell stage and throughout B-cell development (Fig. 1A) [8,9]. The modest activity of each of the 3 0 RR elements, however, contributes to a synergic...

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“…25 Although the Ig heavy-and lightchain enhancers contain binding sites for numerous different classes of transcription factors, Ig gene variable region promoters seem to be less complex and predominantly contain a motif termed the octamer element (59-ATGCAAAT-39), which is located 10-25 nucleotides upstream of the TATA box. The canonical octamer or its reverse complement is conserved in all Ig heavy-and light-chain variable region promoters.…”

Section: Introductionmentioning

confidence: 99%

Distinct regulatory mechanism of immunoglobulin gene transcription in epithelial cancer cells

Zhu

Zhang

et al. 2010

Cell Mol Immunol

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The restriction of immunoglobulin (Ig) expression to B lymphocytes is well established. However, several reports have confirmed that the Ig gene can be expressed in many non-B cancer cells and/or some normal cells. Our aim is to determine whether the Ig gene promoter can be activated in non-B cancer cells and to identify the regulatory mechanism for Ig gene expression. Our results show that the Ig promoter of VH4-59 was activated in several non-B cancer cell lines. Moreover, two novel positive regulatory elements, an enhancer-like element at 2800 to 2610 bp and a copromoter-like element at 2610 to 2300 bp, were identified in two epithelial cancer cell lines, HeLa S3 and HT-29. The octamer element (59-ATGCAAAT-39) located in the Ig promoter, a crucial element for B-cell-derived Ig gene transcription, was also very important for non-B-cell-derived Ig gene transcription. More importantly, we confirmed that octamer-related protein-1 (Oct-1), but not Oct-2, was a crucial transcriptional factor for Ig gene transcription due to its ability to bind to the octamer element of the Ig promoter in epithelial cancer cells. These results suggested the presence of a distinct regulatory mechanism for Ig gene expression in non-B cancer cells.

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Evidence for Physical Interaction between the Immunoglobulin Heavy Chain Variable Region and the 3′ Regulatory Region

Cited by 47 publications

References 36 publications

In Vivo Redundant Function of the 3′ IgH Regulatory Element HS3b in the Mouse

In Vivo Redundant Function of the 3′ IgH Regulatory Element HS3b in the Mouse

The IgH 3′ regulatory region and its implication in lymphomagenesis

Distinct regulatory mechanism of immunoglobulin gene transcription in epithelial cancer cells

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