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

Garot, Armand; Marquet, Marie; Saintamand, Alexis; Bender, Sébastien; Noir, Sandrine Le; Rouaud, Pauline; Carrion, Claire; Oruc, Zéliha; Bébin, Anne-Gaëlle; Cook-Moreau, Jeanne; Lebrigand, Kévin; Denizot, Yves; Alt, Frederick W.; Cogné, Michel; Pinaud, Eric

doi:10.1073/pnas.1514090113

Cited by 27 publications

(32 citation statements)

References 51 publications

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“…However, deletion of the 3′RR in the CH12F3 cell line only modestly reduces CSR to IgA. This apparent discrepancy suggests that the 3′RR likely exerts distinct functions at different stages of B cell development as was also suggested recently (20). An obvious explanation for this difference is that in 3′RR-deleted mice, the 3′RR is absent throughout the B cell development, whereas in CH12F3 cell line, the loss of 3′RR occurs at the brink of CSR.…”

Section: Discussionmentioning

confidence: 58%

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: Discussionmentioning

confidence: 58%

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 3′RR has been widely studied in this model organism, showing that relevant functions for B cell and Ig maturation are associated with this regulatory region (Dunnick et al, ; Pinaud et al, ; Pinaud, Aupetit, Chauveau, & Cogné, ; Volpi et al, ). Finally, results obtained in the mouse (Garot et al, ; Giambra et al, ) indicate that the 3′RR exerts its effects a long way upstream, up to the variable region‐encoding gene segments. In particular, “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 quasi‐palindromic structure” (Garot et al, ).…”

Section: Discussionmentioning

confidence: 97%

Concerted variation of the 3′ regulatory region of Ig heavy chain and Gm haplotypes across human continental populations

Frezza

Martínez-Labarga

Giambra³

et al. 2020

American J Phys Anthropol

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Objectives The 3′ regulatory region of the immunoglobulin heavy chain gene (IGH) includes the HS1.2 enhancer displaying length polymorphism with four known variants. The goal of the research was to provide an overview of this variability and of its evolutionary significance across human populations. Materials and Methods We compiled published and original data on HS1.2 polymorphism in 3,100 subjects from 26 human populations. Moreover, we imputed the haplotypic arrangement of the HS1.2 region in the 1000 Genomes Project (1KGP). In this dataset, imputation could also be obtained for the G1m‐G3m allotype by virtue of the precise correspondence between serological types and amino acid (and DNA) substitutions in IGHG1 and IGHG3. Results HS1.2 variant frequencies displayed similar patterns of continental partitioning as those reported in the literature for the physically neighboring IGHG1‐IGHG3 system. The 1KGP data revealed that linkage disequilibrium (LD) can explain the spread of joint HS1.2‐IGHG1‐IGHG3 associations across continents and within continental populations, with stronger LD out of Africa and the features of an evolutionarily stable genomic block with differential expression in lymphoblastoid cell lines. Discussion Strong population structuring involves at least the entire 70 kb genomic region here considered, due to the tight LD which maintained HS1.2, IGHG1, and IGHG3 in nonrandom arrangements. This might be key to better understand the evolutionary path of the entire genomic region driven by immune response capabilities, during the formation of continental gene pools.

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“…Mice lacking 3′RR are also deficient in SHM and CSR [23,38–40]. The 3′RR not only influences CSR outcome in normal animals, but a rearrangement involving the 3′RR can serve as a mechanism for B cell suicide [41–44]. Polymorphisms in the hs1,2 sequence associate with particular isotype expression patterns in humans, and risks of the female-predominant systemic lupus erythematosus [45].…”

Section: Discussionmentioning

confidence: 99%

Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression

Jones

Penkert

et al. 2016

Molecular Immunology

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Females and males differ in antibody isotype expression patterns and in immune responses to foreign- and self-antigens. For example, systemic lupus erythematosus is a condition that associates with the production of isotype-skewed anti-self antibodies, and exhibits a 9:1 female:male disease ratio. To explain differences between B cell responses in males and females, we sought to identify direct interactions of the estrogen receptor (ER) with the immunoglobulin heavy chain locus. This effort was encouraged by our previous identification of ER response elements (ERE) in heavy chain switch (S) regions. We conducted a full-genome chromatin immunoprecipitation analysis (ChIP-seq) using DNA from LPS-activated B cells and an ERα antibody. Results revealed ER binding to a wide region of DNA, spanning sequences from the JH cluster to Cδ, with peaks in Eμ and Sμ sites. Additional peaks of ERα binding were coincident with hs1,2 and hs4 sites in the 3′ regulatory region (3′RR) of the heavy chain locus. This first demonstration of direct binding of ER to key regulatory elements in the immunoglobulin locus supports our hypothesis that estrogen and other nuclear hormone receptors and ligands may directly influence antibody expression and CSR. Our hypothesis encourages the conduct of new experiments to evaluate the consequences of ER binding. A better understanding of ER:DNA interactions in the immunoglobulin heavy chain locus, and respective mechanisms, may ultimately translate to better control of antibody expression, better protection against pathogens, and prevention of pathologies caused by auto-immune disease.

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

Cited by 27 publications

References 51 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

Concerted variation of the 3′ regulatory region of Ig heavy chain and Gm haplotypes across human continental populations

Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression

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