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Epigenetic Regulation of Monoallelic Rearrangement (Allelic Exclusion) of Antigen Receptor Genes

Published on Dec 5, 2014in Frontiers in Immunology4.716
· DOI :10.3389/fimmu.2014.00625
Rena Levin-Klein5
Estimated H-index: 5
(HUJI: Hebrew University of Jerusalem),
Yehudit Bergman36
Estimated H-index: 36
(HUJI: Hebrew University of Jerusalem)
Abstract
While most genes in the mammalian genome are transcribed from both parental chromosomes in cells where they are expressed, approximately 10% of genes are expressed monoallelically, so that any given cell will express either the paternal or maternal allele, but not both. The antigen receptor genes in B and T cells are well studied examples of a gene family which is expressed in a monoallelic manner, in a process coined "allelic exclusion". During lymphocyte development, only one allele of each antigen receptor undergoes V(D)J rearrangement at a time, and once productive rearrangement is sensed, rearrangement of the second allele is prevented. In this minireview, we discuss the epigenetic processes, including asynchronous replication, nuclear localization, chromatin condensation, histone modifications and DNA methylation, which appear to regulate the primary rearrangement of a single allele, while blocking the rearrangement of the second allele.
  • References (55)
  • Citations (14)
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References55
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#1Rena Levin-Klein (HUJI: Hebrew University of Jerusalem)H-Index: 5
#2Andrei Kirillov (HUJI: Hebrew University of Jerusalem)H-Index: 5
Last. Yehudit Bergman (HUJI: Hebrew University of Jerusalem)H-Index: 36
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The Igκ locus undergoes a variety of different molecular processes during B cell development, including V(D)J rearrangement and somatic hypermutations, which are influenced by cis regulatory regions (RR) within the locus. The Igκ locus includes three characterized RRs termed the intronic (iEκ), 3’Eκ and Ed enhancers. We had previously noted that a region of DNA upstream of the iEκ and matrix attachment region (MAR) was necessary for demethylation of the locus in cell culture. In this study, we f...
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T-cell receptor α (TCRα) chain rearrangement is not constrained by allelic exclusion and thus αβ T cells frequently have rearranged both alleles of this locus. Thereby, stepwise secondary rearrangements of both TCRα loci further increase the odds for generation of an α-chain that can be positively selected in combination with a pre-existing TCRβ chain. Previous studies estimated that approximately 2–12% of murine and human αβ T cells still carry one TCRα locus in germline configuration, which mu...
2 CitationsSource
#1Robert N. Plasschaert (UPenn: University of Pennsylvania)H-Index: 5
#2Marisa S. Bartolomei (UPenn: University of Pennsylvania)H-Index: 58
Genes that are subject to genomic imprinting in mammals are preferentially expressed from a single parental allele. This imprinted expression of a small number of genes is crucial for normal development, as these genes often directly regulate fetal growth. Recent work has also demonstrated intricate roles for imprinted genes in the brain, with important consequences on behavior and neuronal function. Finally, new studies have revealed the importance of proper expression of specific imprinted gen...
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#1Roberta Pelanda (University of Colorado Denver)H-Index: 31
Receptor editing, a major mechanism of B cell tolerance, can also lead to allelic inclusion at the immunoglobulin light chain loci and the development of B cells that coexpress two different immunoglobulin light chains and, therefore, two antibody specificities. Most allelically included B cells express two κ chains, although rare dual-λ cells are also observed. Moreover, these cells typically coexpress an autoreactive and a nonautoreactive antibody. Thus, allelically included B cells could oper...
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Random autosomal monoallelic gene expression refers to the transcription of a gene from one of two homologous alleles. We assessed the dynamics of monoallelic expression during development through an allele-specific RNA-sequencing screen in clonal populations of hybrid mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs). We identified 67 and 376 inheritable autosomal random monoallelically expressed genes in ESCs and NPCs, respectively, a 5.6-fold increase upon differentiation. ...
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Summary X chromosome inactivation (XCI) and allelic exclusion of olfactory receptors or immunoglobulin loci represent classic examples of random monoallelic expression (RME). RME of some single copy genes has also been reported, but the in vivo relevance of this remains unclear. Here we identify several hundred RME genes in clonal neural progenitor cell lines derived from embryonic stem cells. RME occurs during differentiation, and, once established, the monoallelic state can be highly stable. W...
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Expression from both alleles is generally observed in analyses of diploid cell populations, but studies addressing allelic expression patterns genome-wide in single cells are lacking. Here, we present global analyses of allelic expression across individual cells of mouse preimplantation embryos of mixed background (CAST/EiJ × C57BL/6J). We discovered abundant (12 to 24%) monoallelic expression of autosomal genes and that expression of the two alleles occurs independently. The monoallelic express...
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Allelic exclusion requires that the two alleles at antigen-receptor loci attempt to recombine variable (V), diversity (D), and joining (J) gene segments [V(D)J recombination] asynchronously in nuclei of developing lymphocytes. It previously was shown that T-cell receptor β (Tcrb) alleles frequently and stochastically associate with the nuclear lamina and pericentromeric heterochromatin in CD4−CD8− thymocytes. Moreover, rearranged alleles were underrepresented at these locations. Here we used 3D ...
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Summary DNA methylation was described almost a century ago. However, the rules governing its establishment and maintenance remain elusive. Here, we present data demonstrating that active transcription regulates levels of genomic methylation. We identified a novel RNA arising from the CEBPA gene locus critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome...
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#1Ivan Rodriguez (University of Geneva)H-Index: 34
Understanding the mechanisms of monogenic and monoallelic transcription of the large repertoire of olfactory receptor genes represents a challenging task. A picture is now emerging in which odorant receptor choice and stabilization involve an escape from silencing followed by the activation of an unconventional feedback loop.
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The monoallelic expression of antigen receptor (AgR) genes, called allelic exclusion, is fundamental for highly specific immune responses to pathogens. This cardinal feature of adaptive immunity is achieved by the assembly of a functional AgR gene on one allele, with subsequent feedback inhibition of V(D)J recombination on the other allele. A range of epigenetic mechanisms have been implicated in sequential recombination of AgR alleles; however, we now demonstrate that a genetic mechanism contro...
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