NF‐κB binds to the immunoglobulin Sγ3 region <i>in vivo</i> during class switch recombination

Wang, Lili; Wuerffel, Robert; Kenter, Amy L.

doi:10.1002/eji.200636294

Cited by 14 publications

(16 citation statements)

References 49 publications

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“…It is noteworthy that p50 Ϫ/Ϫ cells are deficient in normal GT and in CSR (46), suggesting that the shift in Pax5 binding away from hs4 and back again are requirements for normal GT and CSR. It is of interest that the NFB and Pax5 binding sites are located 20 bp apart in hs4 (25), raising the possibility that engagement of one of these factors might affect occupancy of the other.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Changes in Binding of Immunoglobulin Heavy Chain 3′ Regulatory Region to Protein Factors during Class Switching

Chatterjee

Zhang

Hassan

et al. 2011

Journal of Biological Chemistry

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The 3 regulatory region (3 RR) of the Igh locus works at long distances on variable region (V H ) and switch region (I) region promoters to initiate germ line (non-coding) transcription (GT) and promote class switch recombination (CSR). The 3 RR contains multiple elements, including enhancers (hs3a, hs1.2, hs3b, and hs4) and a proposed insulator region containing CTCF (CCCTC-binding factor) binding sites, i.e. hs5/6/7 and the downstream region ("38"). Notably, deletion of each individual enhancer (hs3a-hs4) has no significant phenotypic consequence, suggesting that the 3 RR has considerable structural flexibility in its function. To better understand how the 3 RR functions, we identified transcription factor binding sites and used chromatin immunoprecipitation (ChIP) assays to monitor their occupancy in splenic B cells that initiate GT and undergo CSR (LPS؎IL4), are deficient in GT and CSR (p50 ؊/؊ ), or do not undergo CSR despite efficient GT (anti-IgM؉IL4). Like 3 RR enhancers, hs5-7 and the 38 region were observed to contain multiple Pax5 binding sites (in addition to multiple CTCF sites). We found that the Pax5 binding profile to the 3 RR dynamically changed during CSR independent of the specific isotype to which switching was induced, and binding focused on hs1.2, hs4, and hs7. CTCF-associated and CTCF-independent cohesin interactions were also identified. Our observations are consistent with a scaffold model in which a platform of active protein complexes capable of facilitating GT and CSR can be formed by varying constellations of 3 RR elements.The immunoglobulin heavy chain (Igh) 3 locus is subject to multiple processes that markedly increase the number of different antibody gene coding sequences (reviewed in Ref. 1). These include the random DNA recombination of V (variable), D (diversity) and J (joining) sequences to form multiple variable region coding segments and class switch recombination (CSR) that juxtaposes assembled variable region genes to different constant region (C H ) genes to provide distinct biological functions associated with specific antigen-binding specificities. In addition, somatic hypermutation of variable region genes augments genetic diversity. These processes are regulated by cisacting elements, including locally acting promoters, and by long distance regulators, such as the intronic enhancer (E) and the 3Ј regulatory region (3Ј RR). Knockout mouse models identified E as a major regulator of VDJ recombination (2-5) and showed that the 3Ј RR influenced germ line (non-coding) transcription (GT) of individual C H genes (6 -11). GT is initiated from a promoter upstream of each C H gene and extends through switch and C H sequences, generating a single-stranded DNA substrate for activation-induced cytidine deaminase (AID), a protein critical for CSR (12). Long-range physical interactions between an element of the 3Ј RR and I region promoters that drive GT have been shown in cells stimulated by LPS to undergo CSR by use of a chromosome conformation capture (3C) assay (13). Studies hav...

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Section: Discussionmentioning

confidence: 99%

Dynamic Changes in Binding of Immunoglobulin Heavy Chain 3′ Regulatory Region to Protein Factors during Class Switching

Chatterjee

Zhang

Hassan

et al. 2011

Journal of Biological Chemistry

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“…However, selection partially corrected the defect in exonucleolytic processing, resulting in a lesser abnormality in the productive repertoire. It is well-established that NF-B regulates different aspects of B cell apoptosis (2,9,12), proliferation (10,11,48), maturation (6, 9, 13, 49 -51), survival (8,49,52), class switch and Ig gene recombination (11,14,23,35,(53)(54)(55)(56)(57). In vitro studies examining Ikk␥ Ϫ/Ϫ embryonic stem cells cocultured with bone marrow cells (52) and in vivo studies using Mb-1Cre-transgenic mice lacking Ikk␥ from the B cell progenitor stage on (48) Previous studies have shown that NF-B signaling is defective in B cells of HED-ID patients (50).…”

Section: Discussionmentioning

confidence: 99%

The NF-κB Canonical Pathway Is Involved in the Control of the Exonucleolytic Processing of Coding Ends during V(D)J Recombination

Souto-Carneiro

Fritsch

Sepúlveda

et al. 2008

The Journal of Immunology

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V(D)J recombination is essential to produce an Ig repertoire with a large range of Ag specificities. Although NF-κB-binding sites are present in the human and mouse IgH, Igκ, and Igλ enhancer modules and RAG expression is controlled by NF-κB, it is not known whether NF-κB regulates V(D)J recombination mechanisms after RAG-mediated dsDNA breaks. To clarify the involvement of NF-κB in human V(D)J recombination, we amplified Ig gene rearrangements from individual peripheral B cells of patients with X-linked anhidrotic ectodermal dysplasia with hyper-IgM syndrome (HED-ID) who have deficient expression of the NF-κB essential modulator (NEMO/Ikkγ). The amplification of nonproductive Ig gene rearrangements from HED-ID B cells reflects the influence of the Ikkγ-mediated canonical NF-κB pathway on specific molecular mechanisms involved in V(D)J recombination. We found that the CDR3H from HED-ID B cells were abnormally long, as a result of a marked reduction in the exonuclease activity on the V, D, and J germline coding ends, whereas random N-nucleotide addition and palindromic overhangs (P nucleotides) were comparable to controls. This suggests that an intact canonical NF-κB pathway is essential for normal exonucleolytic activity during human V(D)J recombination, whereas terminal deoxynucleotide transferase, Artemis, and DNA-dependent protein kinase catalytic subunit activity are not affected. The generation of memory B cells and somatic hypermutation were markedly deficient confirming a role for NF-κB in these events of B cell maturation. However, selection of the primary B cell repertoire appeared to be intact and was partially able to correct the defects generated by abnormal V(D)J recombination.

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“…NF-B p50 is critical for the germ line C H ␥3 transcription in response to stimulation and likely mediates chromatin remodeling at the S␥3 and S␥1 region through direct binding (72,82). Administration of the T-dependent nitrophenol-conjugated keyhole limpet hemocyanin immunogen to p50 Ϫ/Ϫ mice leads to smaller and decreased numbers of germinal centers (59,60).…”

Section: /P50mentioning

confidence: 99%

NF-κB p50 Plays Distinct Roles in the Establishment and Control of Murine Gammaherpesvirus 68 Latency

Krug

Collins

Gargano

et al. 2009

J Virol

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NF-B signaling is critical to the survival and transformation of cells infected by the human gammaherpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. Here we have examined how elimination of the NF-B transcription factor p50 from mice affects the life cycle of murine gammaherpesvirus 68 (MHV68). Notably, mice lacking p50 in every cell type were unable to establish a sufficiently robust immune response to control MHV68 infection, leading to high levels of latently infected B cells detected in the spleen and persistent virus replication in the lungs. The latter correlated with very low levels of virus-specific immunoglobulin G (IgG) in the infected p50 ؊/؊ mice at day 48 postinfection. Because the confounding impact of the loss of p50 on the host response to MHV68 infection prevented a direct analysis of the role of this NF-B family member on MHV68 latency in B cells, we generated and infected mixed p50 ؉/؉ /p50 ؊/؊ bone marrow chimeric mice. We show that the chimeric mice were able to control acute virus replication and exhibited normal levels of virus-specific IgG at 3 months postinfection, indicating the induction of a normal host immune response to MHV68 infection. However, in p50 ؉/؉ /p50 ؊/؊ chimeric mice the p50 ؊/؊ B cells exhibited a significant defect compared to p50 ؉/؉ B cells in supporting MHV68 latency. In addition to identifying a role for p50 in the establishment of latency, we determined that the absence of p50 in a subset of the hematopoietic compartment led to persistent virus replication in the lungs of the chimeric mice, providing evidence that p50 is required for controlling virus reactivation. Taken together, these data demonstrate that p50 is required for immune control by the host and has distinct tissue-dependent roles in the regulation of murine gammaherpesvirus latency during chronic infection.Murine gammaherpesvirus 68 (MHV68) is a natural pathogen of rodents and shares many biologic properties with the human pathogens Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). As a gammaherpesvirus, MHV68 is lymphotropic and is associated with pathologies and neoplasia that increase upon loss of host immune control (21,56,75). Chronic infection with MHV68 initiates with an acute productive phase of infection and dissemination to secondary lymphoid tissues, leading to the establishment of a quiescent latent virus program in B cells and ultimately memory B cells, with intermittent reactivation events that are controlled by the immune system (27,56,87). The genetic tractability of MHV68 and the murine host permit a molecular dissection of key factors and signaling pathways required for chronic infection by the virus, in addition to those processes utilized for immune control by the host (29). NF-B signaling is one host pathway that is utilized by gammaherpesviruses to promote latency and cell survival (8,18,40,65).Gammaherpesviruses encode numerous gene products that hijack NF-B signaling by distinct mechanisms to regulate virus and host gene ex...

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NF‐κB binds to the immunoglobulin Sγ3 region in vivo during class switch recombination

Cited by 14 publications

References 49 publications

Dynamic Changes in Binding of Immunoglobulin Heavy Chain 3′ Regulatory Region to Protein Factors during Class Switching

Dynamic Changes in Binding of Immunoglobulin Heavy Chain 3′ Regulatory Region to Protein Factors during Class Switching

The NF-κB Canonical Pathway Is Involved in the Control of the Exonucleolytic Processing of Coding Ends during V(D)J Recombination

NF-κB p50 Plays Distinct Roles in the Establishment and Control of Murine Gammaherpesvirus 68 Latency

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