Allelic Exclusion of IgH through Inhibition of E2A in a VDJ Recombination Complex

Hauser, Jannek; Grundström, C.; Grundström, Thomas

doi:10.4049/jimmunol.1302216

Cited by 10 publications

(10 citation statements)

References 53 publications

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“…It is particularly important for the Igh or Tcrb loci that accessibility is reduced in pre-B and DP cells as RAG expression is once again up-regulated and this could potentially target unrearranged alleles during Igk/Igl and Tcra recombination, respectively that could then lead to allelic inclusion. There are many transcription factors involved in regulating rearrangement but only a few (for example E2A) which are reported to function in allelic exclusion (Hauser et al, 2014). In DN thymocytes E2A binds to the Tcrb DJβ region, Eβ and some Vβ gene promoters and activates germ-line transcription (Belle and Zhuang, 2014).…”

Section: Allelic Exclusionmentioning

confidence: 99%

Long-Range Regulation of V(D)J Recombination

Proudhon

Hao

Raviram

et al. 2015

Advances in Immunology

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Given their essential role in adaptive immunity, antigen receptor loci have been the focus of analysis for many years and are among a handful of the most well studied genes in the genome. Their investigation led initially to a detailed knowledge of linear structure and characterization of regulatory elements that confer control of their rearrangement and expression. However, advances in DNA FISH and imaging combined with new molecular approaches that interrogate chromosome conformation have led to a growing appreciation that linear structure is only one aspect of gene regulation and in more recent years the focus has switched to analyzing the impact of locus conformation and nuclear organization on control of recombination. Despite decades of work and intense effort from numerous labs we are still left with an incomplete picture of how antigen receptor loci are regulated. This chapter summarizes our advances to date and points to areas that need further investigation.

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Section: Allelic Exclusionmentioning

confidence: 99%

Long-Range Regulation of V(D)J Recombination

Proudhon

Hao

Raviram

et al. 2015

Advances in Immunology

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“…One of the control proteins that could not recruit AID to the DNA with PAX5 binding site was the transcription factor E2A (Fig. A) that has been shown to be important for antibody gene expression and has been implicated in somatic hypermutation and class switch recombination ( and references therein). Another of the control proteins that could not recruit AID to the DNA with PAX5 binding site was the transcription factor ETS1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We showed also that the complex is redistributed on the Igh locus upon B cell receptor (BCR) signalling that terminates SH but not CSR. We have also previously reported direct interactions between purified AID, E2A and PAX5 in vitro and that the interactions are through the paired homology domain (PD) of PAX5 and the basic‐helix‐loop‐helix (bHLH) domain of E2A .…”

Section: Introductionmentioning

confidence: 89%

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ETS1 and PAX5 transcription factors recruit AID to Igh DNA

et al. 2018

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B lymphocytes optimize antibody responses by class switch recombination (CSR), which changes the expressed constant region exon of the immunoglobulin heavy chain (IgH), and by somatic hypermutation (SH) that introduces point mutations in the variable regions of the antibody genes. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates both these antibody diversification processes by deaminating cytosine to uracil. Here we asked the question if transcription factors can mediate the specific targeting of the antibody diversification by recruiting AID. We have recently reported that AID is together with the transcription factors E2A, PAX5 and IRF4 in a complex on key sequences of the Igh locus. Here we report that also ETS1 is together with AID in this complex on key sequences of the Igh locus in splenic B cells of mice. Furthermore, we show that both ETS1 and PAX5 can directly recruit AID to DNA sequences from the Igh locus with the specific binding site for the transcription factor. Taken together, our findings support the notion of a targeting mechanism for the selective diversification of antibody genes with limited genome wide mutagenesis by recruitment of AID by PAX5 and ETS1 in a transcription factor complex.

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“…For semi-quantitative real-time PCR, the reaction was performed with FastStart Essential DNA Green Master (Roche) on a LightCycler Nano System (Roche). The PCR primers were described previously [16,17]. The PCR profile was as follows: 95°C for 10 min, 45 cycles of 95°C for 10 sec and 60°C for 30 sec, and the melting curve analysis was performed to verify the amplification specificity.…”

Section: Methodsmentioning

confidence: 99%

Epigenetic silencing of V(D)J recombination is a major determinant for selective differentiation of mucosal-associated invariant t cells from induced pluripotent stem cells

et al. 2017

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Mucosal-associated invariant T cells (MAITs) are innate-like T cells that play a pivotal role in the host defense against infectious diseases, and are also implicated in autoimmune diseases, metabolic diseases, and cancer. Recent studies have shown that induced pluripotent stem cells (iPSCs) derived from MAITs selectively redifferentiate into MAITs without altering their antigen specificity. Such a selective differentiation is a prerequisite for the use of MAITs in cell therapy and/or regenerative medicine. However, the molecular mechanisms underlying this phenomenon remain unclear. Here, we performed methylome and transcriptome analyses of MAITs during the course of differentiation from iPSCs. Our multi-omics analyses revealed that recombination-activating genes (RAG1 and RAG2) and DNA nucleotidylexotransferase (DNTT) were highly methylated with their expression being repressed throughout differentiation. Since these genes are essential for V(D)J recombination of the T cell receptor (TCR) locus, this indicates that nascent MAITs are kept from further rearrangement that may alter their antigen specificity. Importantly, we found that the repression of RAGs was assured in two layers: one by the modulation of transcription factors for RAGs, and the other by DNA methylation at the RAG loci. Together, our study provides a possible explanation for the unaltered antigen specificity in the selective differentiation of MAITs from iPSCs.

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Allelic Exclusion of IgH through Inhibition of E2A in a VDJ Recombination Complex

Cited by 10 publications

References 53 publications

Long-Range Regulation of V(D)J Recombination

Long-Range Regulation of V(D)J Recombination

ETS1 and PAX5 transcription factors recruit AID to Igh DNA

Epigenetic silencing of V(D)J recombination is a major determinant for selective differentiation of mucosal-associated invariant t cells from induced pluripotent stem cells

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