Mediator facilitates transcriptional activation and dynamic long-range contacts at the IgH locus during class switch recombination

Thomas-Claudepierre, Anne Sophie; Robert, Isabelle; Rocha, Pedro P.; Raviram, Ramya; Schiavo, Ebe; Heyer, Vincent; Bonneau, Richard; Luo, Vincent; Reddy, Janardan K.; Borggrefe, Tilman; Skok, Jane A.; Reina‐San‐Martin, Bernardo

doi:10.1084/jem.20141967

Cited by 37 publications

(43 citation statements)

References 31 publications

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“…The large number of 5′hs1RI Δ alleles transcribing Sγ3 before LPS stimulation suggests that the Iγ3 promoter already lies in close proximity to the 3′RR at this time. Indeed, chromosome conformation capture studies detected a relatively high frequency of cross-linking between the 3′RR and Iγ3 in resting B cells (21)(22)(23). These findings are consistent with a model in which the Iγ3 promoter is first activated due to its proximity to the 3′RR (15), while Iγ2b is recruited to the 3′RR-Iγ3 hub after LPS stimulation only.…”

Section: Discussionsupporting

confidence: 83%

Two modes ofcis-activation of switch transcription by theIgHsuperenhancer

Santos

Braikia

Oudinet

et al. 2019

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

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B cell isotype switching plays an important role in modulating adaptive immune responses. It occurs in response to specific signals that often induce different isotype (I) promoters driving transcription of switch regions, located upstream of the Ig heavy chain (IgH) constant genes. The transcribed switch regions can recombine, leading to a change of the constant gene and, consequently, of antibody isotype. Switch transcription is controlled by the superenhancer 3′ regulatory region (3′RR) that establishes long-range chromatin cis-interactions with I promoters. Most stimuli induce more than one I promoter, and switch transcription can occur on both chromosomes. Therefore, it is presently unknown whether induced I promoters compete for the 3′RR on the same chromosome. Here we performed single-chromosome RT-qPCR assays to examine switch transcription monoallelically in the endogenous context. We show that there are two modes of 3′RR-mediated activation of I promoters: coactivation and competition. The nature of the inducing signal plays a pivotal role in determining the mode of activation. Furthermore, we provide evidence that, in its endogenous setting, the 3′RR has a bidirectional activity. We propose that the coactivation and competition modes mediated by the 3′RR may have evolved to cope with the different kinetics of primary immune responses.

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Section: Discussionsupporting

confidence: 83%

Two modes ofcis-activation of switch transcription by theIgHsuperenhancer

Santos

Braikia

Oudinet

et al. 2019

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

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“…This discrepancy could result from different activation conditions: αCD40 + IL4 versus LPS + IL4. When we used the same 4C primers in an experiment in which B cells were activated with LPS + IL4, we also found an increase in the interaction between Eμ and the 3RR ( Thomas-Claudepierre et al, 2016 ). It is known that activation under these conditions results in differences in targeting of switch regions: LPS with IL4 induces DSBs at Sγ3, Sγ1, and Sε, while αCD40 + IL4 results in targeting of Sγ1 and Sε.…”

Section: Resultsmentioning

confidence: 73%

A Damage-Independent Role for 53BP1 that Impacts Break Order and Igh Architecture during Class Switch Recombination

Rocha

Raviram

et al. 2016

Cell Reports

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SUMMARYDuring class switch recombination (CSR), B cells replace the Igh Cμ or δ exons with another down-stream constant region exon (CH), altering the anti-body isotype. CSR occurs through the introduction of AID-mediated double-strand breaks (DSBs) in switch regions and subsequent ligation of broken ends. Here, we developed an assay to investigate the dynamics of DSB formation in individual cells. We demonstrate that the upstream switch region Sμ is first targeted during recombination and that the mechanism underlying this control relies on 53BP1. Surprisingly, regulation of break order occurs through residual binding of 53BP1 to chromatin before the introduction of damage and independent of its established role in DNA repair. Using chromosome conformation capture, we show that 53BP1 mediates changes in chromatin architecture that affect break order. Finally, our results explain how changes in Igh architecture in the absence of 53BP1 could promote inversional rearrangements that compromise CSR.

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“…There were also peaks in immunoglobulin light chain and TCR loci (Supplementary Figure 5) (71-74). HS4, HS1,2 and Eµ enhancers have been studied extensively and shown to influence the chromatin looping/remodeling required for CSR, and immunoglobulin heavy chain gene expression (51,(75)(76)(77)(78).…”

Section: Erα Binding In the Heavy Chain Locus Of B Cells Stimulated Wmentioning

confidence: 99%

Complex sex-biased antibody responses: estrogen receptors bind estrogen response elements centered within immunoglobulin heavy chain gene enhancers

Jones

Sealy

Penkert

et al. 2018

International Immunology

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Nuclear hormone receptors including the estrogen receptor (ERα) and the retinoic acid receptor regulate a plethora of biological functions including reproduction, circulation and immunity. To understand how estrogen and other nuclear hormones influence antibody production, we characterized total serum antibody isotypes in female and male mice of C57BL/6J, BALB/cJ and C3H/HeJ mouse strains. Antibody levels were higher in females compared to males in all strains and there was a female preference for IgG2b production. Sex-biased patterns were influenced by vitamin levels, and by antigen specificity toward influenza virus or pneumococcus antigens. To help explain sex biases, we examined the direct effects of estrogen on immunoglobulin heavy chain sterile transcript production among purified, lipopolysaccharide-stimulated B cells. Supplemental estrogen in B-cell cultures significantly increased immunoglobulin heavy chain sterile transcripts. Chromatin immunoprecipitation analyses of activated B cells identified significant ERα binding to estrogen response elements (EREs) centered within enhancer elements of the immunoglobulin heavy chain locus, including the Eµ enhancer and hypersensitive site 1,2 (HS1,2) in the 3′ regulatory region. The ERE in HS1,2 was conserved across animal species, and in humans marked a site of polymorphism associated with the estrogen-augmented autoimmune disease, lupus. Taken together, the results highlight: (i) the important targets of ERα in regulatory regions of the immunoglobulin heavy chain locus that influence antibody production, and (ii) the complexity of mechanisms by which estrogen instructs sex-biased antibody production profiles.

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Mediator facilitates transcriptional activation and dynamic long-range contacts at the IgH locus during class switch recombination

Abstract: Thomas-Claudepierre et al. report that mediator facilitates the long-range contacts between acceptor switch regions and the IgH locus enhancers during class switch recombination and their transcriptional activation.

Cited by 37 publications

References 31 publications

Two modes ofcis-activation of switch transcription by theIgHsuperenhancer

Two modes ofcis-activation of switch transcription by theIgHsuperenhancer

A Damage-Independent Role for 53BP1 that Impacts Break Order and Igh Architecture during Class Switch Recombination

Complex sex-biased antibody responses: estrogen receptors bind estrogen response elements centered within immunoglobulin heavy chain gene enhancers

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