Enhancement of Antibody Class-Switch Recombination by the Cumulative Activity of Four Separate Elements

Dunnick, Wesley A.; Shi, Jian; Zerbato, Jennifer M.; Fontaine, Clinton; Collins, John T.

doi:10.4049/jimmunol.1101808

Cited by 15 publications

(20 citation statements)

References 41 publications

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“…5A, B). The choice of this DNA fragment was based on elegant studies showing that deletion of the four HS sites on a BAC transgene inhibits GLT and CSR to the same degree as the deletion of the entire 3’RR (19). Although the spacer regions were not deemed dispensable, it appears that the primary regulatory elements are located within these enhancers.…”

Section: Resultsmentioning

confidence: 99%

Class-Switch Recombination in the Absence of the IgH 3′ Regulatory Region

Kim

Han

Santiago

et al. 2016

The Journal of Immunology

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The ~28 kb 3′-regulatory region (3′RR) which is located at the most distal 3′ region of the immunoglobulin (Ig) heavy (H) chain locus has multiple regulatory functions that control IgH expression, class switch recombination (CSR) and somatic hypermutation (SHM). Here, we report that deletion of the entire 3′RR in a mouse B cell line that is capable of robust cytokine-dependent CSR to IgA results in reduced but not abolished CSR. These data suggest that the 3′RR is not absolutely required for CSR, and thus is not essential for targeting AID to S regions as has been suggested. Moreover, replacing the 3′RR with a DNA fragment including only its four DNase I hypersensitive sites (lacking the large spacer regions), restores CSR to a level equivalent to or even higher than wild type cells, suggesting that the four HS sites contain most of the CSR-promoting functions of the 3′RR. Stimulated cells express abundant germline transcripts, with the presence or absence of the 3′RR, providing evidence that the 3’RR has a separate role in promoting CSR, that is unique from enhancing S region transcription.

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Section: Resultsmentioning

confidence: 99%

Class-Switch Recombination in the Absence of the IgH 3′ Regulatory Region

Kim

Han

Santiago

et al. 2016

The Journal of Immunology

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“…GSE76217). Taking CSR into account, bacterial artificial chromosome transgene studies point out a cumulative activity of IgH 3′ enhancer elements, with special activities for some of them, such as hs1-2, hs4 alone or combined with hs3b (23,24), and on the other hand, exonerate any effect of the hs3 homologs (25). Transgenic models contradict endogenous deletion studies with regards to BCR expression and antibody secretion (23).…”

Section: Significancementioning

confidence: 99%

“…Taking CSR into account, bacterial artificial chromosome transgene studies point out a cumulative activity of IgH 3′ enhancer elements, with special activities for some of them, such as hs1-2, hs4 alone or combined with hs3b (23,24), and on the other hand, exonerate any effect of the hs3 homologs (25). Transgenic models contradict endogenous deletion studies with regards to BCR expression and antibody secretion (23). From endogenous deletion models, we learned that 3′RR enhancers share redundant functions because individual KOs had no significant consequences on B-cell remodeling events (26)(27)(28), whereas combined deletion of hs3b and hs4 decreased CSR to all isotypes, except for IgG1 (29).…”

Section: Significancementioning

confidence: 99%

Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

Garot

Marquet

Saintamand

et al. 2016

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

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As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3′ regulatory region (3′RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3′RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasipalindromic structure. By comparing relevant previous knockout (KO) mouse models (3′RR KO and hs3b-4 KO) to a novel mutant devoid of the 3′RR quasi-palindromic region (3′PAL KO), we pinpointed common features and differences that specify two distinct regulatory entities acting sequentially during B-cell ontogeny. Independently of exogenous antigens, the 3′RR distal part, including hs4, fine-tuned B-cell receptor expression in newly formed and naïve B-cell subsets. At mature stages, the 3′RR portion including the quasi-palindrome dictated antigen-dependent locus remodeling (global somatic hypermutation and class switch recombination to major isotypes) in activated B cells and antibody production in plasma cells.immunoglobulin gene regulation | enhancers | B-cell development I mmunoglobulin heavy chain (IgH) expression is critical for B-cell development and survival. In developing B-lineage cells, accessibility to the major remodeling events [VDJ recombination, somatic hypermutation (SHM), class switch recombination (CSR), and locus suicide recombination] depends on epigenetic changes and germ-line transcription of many regions, including V H promoters, I/switch region promoters, cis-regulatory region enhancers, and chromatin insulators (1-3). A focus on knockout (KO) models for IgH cis-regulatory regions (enhancers and chromatin insulators) is a means to simplify the regulation picture. At the preproB stage, the IgH locus undergoes long-range looping in a "rosette-like" structure that brings into close proximity major IgH regulatory regions, such as the V H to D H intergenic control regions (IGCR1 and -2), the Eμ intronic enhancer, the 3′ regulatory region (3′RR), and the 3′IgH CTCF-binding elements (CBEs) (4-6). Initiation of VDJ recombination is assisted by the Eμ enhancer, which provides efficient transcription and accessibility to initiate D H to J H rearrangements (7-10), as well as the IGCR1 and -2 elements that ordinate the V H to DJ H second recombination step (5, 11-13). Devoid of enhancer activity (14, 15), 3′CBE (hs5 to hs8) likely participate in IgH folding before VDJ recombination because deletion of hs5 to -7 only impacts use of proximal V H regions (16). In pre-B cells, once a functional H chain is expressed as a component of the pre-B-cell recptor (BCR), the Eμ enhancer function switches from DJ H region accessibility to Igμ chain expression, and consequent...

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“…The hs1.2 enhancer is part of a large transcriptional regulatory region (3′ IGH RR) that is located 3′ of the heavy chain constant regions in the IGH gene. In animal models and cell culture, this region is crucial for Ig expression and class switch recombination, which impacts overall antibody levels [13-16]. Therefore, the hs1.2 enhancer may influence the expression of CD-associated antibodies and be an additional contributing factor to the currently known genetic risk factors for CD [21].…”

Section: Discussionmentioning

confidence: 99%

“…This potential additional factor is allele 2 of the hs1.2 enhancer within the 3′ IGH regulatory region (3′ IGH RR). In animal models and cell culture, this region is crucial for Ig expression and class switch recombination, which impacts antibody concentrations [13-16]. In humans, the hs1.2 enhancer is polymorphic but the polymorphism is not defined by a single nucleotide polymorphism (SNP).…”

Section: Introductionmentioning

confidence: 99%

Allelic frequencies of the hs1.2 enhancer within the immunoglobulin heavy chain region in Dayton, Ohio patients screened for celiac disease with duodenal biopsy

Liu

Law

Koles

et al. 2017

Digestive and Liver Disease

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Background Genetic and environmental factors contribute to the development of celiac disease (CD), but specific genetic predisposing factors remain poorly understood. One candidate is allele 2 of the hs1.2 enhancer within the immunoglobulin heavy chain region. In humans, there are four possible alleles and a previous study of an Italian cohort demonstrated a significantly increased frequency of allele 2 in patients with CD. Aims The purpose of the current study was to determine if a similar association between allele 2 and CD exists in an American population from Dayton, OH. Methods Subjects were screened for CD via esophagogastroduodenoscopy with duodenal biopsy. All biopsies were microscopically scored using a modified Marsh-Oberhuber classification. DNA was isolated from patients' buccal cells for hs1.2 genotype analysis using PCR. Results Unlike the Italian cohort, allele 2 frequency was not significantly different in patients with histopathologic evidence of CD compared to patients without such evidence. However, our patient population as a whole demonstrated a significantly increased allele 2 frequency when compared to that previously reported within diverse ethnic populations. Conclusions Since our comparative control patients do not necessarily reflect a healthy control population, an overall increase in allele 2 may reflect an association between allele 2 of the hs1.2 enhancer and a spectrum of gastrointestinal disorders.

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Enhancement of Antibody Class-Switch Recombination by the Cumulative Activity of Four Separate Elements

Cited by 15 publications

References 41 publications

Class-Switch Recombination in the Absence of the IgH 3′ Regulatory Region

Class-Switch Recombination in the Absence of the IgH 3′ Regulatory Region

Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

Allelic frequencies of the hs1.2 enhancer within the immunoglobulin heavy chain region in Dayton, Ohio patients screened for celiac disease with duodenal biopsy

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