Choreography of Ig allelic exclusion

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Allelic exclusion guarantees that each B or T cell only produces a single antigen receptor, and in this way contributes to immune diversity. This process is actually initiated in the early embryo when the immune receptor loci become asynchronously replicating in a stochastic manner with one early and one late allele in each cell. This distinct differential replication timing feature then serves an instructive mark that directs a series of allele-specific epigenetic events in the immune system, including programmed histone modification, nuclear localization and DNA demethylation that ultimately bring about preferred rearrangement on a single allele, and this decision is temporally stabilized by feedback mechanisms that inhibit recombination on the second allele. In principle, these same molecular components are also used for controlling monoallelic expression at other genomic loci, such as those carrying interleukins and olfactory receptor genes that require the choice of one gene out of a large array. Thus, allelic exclusion appears to represent a general epigenetic phenomenon that is modeled on the same basis as X chromosome inactivation.

Introduction

Monoallelic expression can be either imprinted or random. Imprinted genes are expressed exclusively from either the maternally or paternally inherited chromosome, with the identity of the expressed allele being predetermined, usually by the establishment of differential DNA methylation in the male or female gametes [1]. Random monoallelic genes, on the other hand, are expressed from the maternal chromosome in some cells and the paternal chromosome in others. The best-known example of this phenomenon is X chromosome inactivation in female cells [2]. In this case, the choice of which X chromosome undergoes silencing is made early in embryonic development and is random. Once established, however, this decision is clonally inherited, resulting in adult females with mosaic expression of X-linked genes from maternally and paternally inherited X chromosomes. In addition to the X chromosome, an increasing number of random monoallelic regions are being identified on autosomes, and these usually contain multi-gene sequence arrays such as olfactory [3] or natural killer cell [4] receptors, interleukins [5, 6, 7, 8], T-cell receptors (TCR) and immunoglobulins (Ig) [9, 10]. In this review, we will discuss the molecular mechanisms that play a role in regulating monoallelic expression of immunoglobulin genes.

Section snippets

Developmental-specific regulation of antigen receptor gene rearrangement

The generation of B or T cell antigen receptors takes place through a multi-step ordered process that involves developmentally regulated rearrangement events. In the B lineage, for example, this begins at the pro-B cell stage with rearrangement of the IgH locus, and light chain genes only rearrange after progression to the pre-B cell stage. Within the heavy chain locus itself DH segments are first joined to JH segments and this is then followed by VH-to-DJH recombination (reviewed in [11]).

Chromatin modification

One of the major ways for controlling accessibility to the recombination machinery is through histone modification (reviewed in [12, 13, 17, 18, 19]). In B cells, for example, both the heavy and light chain loci undergo a series of chromatin changes in which they become hyperacetylated in histones H3 and H4, hypomethylated at H3K9 and enriched for histone H3K4me2,3, and all of these events take place before V(D)J rearrangement [18, 19, 20, 21, 22]. Much like recombination itself, these changes

Non-coding RNA

Over 20 years ago it was observed that initiation of V(D)J recombination often coincides with non-coding (germline) transcription at antigen receptor loci [14], and since this usually appeared before rearrangement, it was suggested that it may be an essential precursor for efficient recombination. The most compelling evidence for this model has been obtained from studies on the TCRα locus where it has been shown that specific blockage of transcriptional elongation suppresses Vα-to-Jα

Stochastic allelic exclusion can be fortuitous or instructive

Allelic exclusion of the immunoglobulin genes is regulated at the level of V(D)J recombination, and two possible mechanisms have been proposed to account for this phenomenon. The first model suggests that monoallelic rearrangement comes about in a fortuitous manner because of low frequency activation and stochastic usage of the two equivalent alleles in pre-B cells (Figure 1a) [35, 36]. Alternatively, the initial decision that differentiates between the two alleles may be carried out in a

Initiation of allelic exclusion

The entire genome is organized into chromosomal bands programmed to replicate at different points in S-phase. In a truly striking manner, expressed genes replicate in early S, while repressed domains replicate late [38]. In keeping with this pattern, genes that are expressed monoallelically at some stage in development have an intermediate pattern, with one allele undergoing replication relatively early in S-phase, while the second allele replicates late. Indeed, this behavior is the hallmark

Epigenetic changes associated with allelic exclusion

Even though rearrangement of each receptor antigen appears to occur at a specific stage in B or T cell development, this event is often preceded by distinct epigenetic changes that, in some instances, have been shown to occur monoallelically in each cell. An excellent example of this is the Igκ light chain locus. During the pro-B cell stage, both alleles of this locus are found at centrally located, indistinguishable positions within the nucleus, but as cells progress to the pre-B cell stage,

Maintenance of allelic exclusion

Once an initial rearrangement event has occurred, there appear to be several different feedback mechanisms that play a role in preventing simultaneous recombination of the second allele, as well as further rearrangements during later stages of B or T cell development. At the IgH locus, for example, successful V(D)J rearrangement of one allele brings about membrane signaling through the generation of a pre-B cell receptor that sets in motion a number of key molecular mechanisms (reviewed in [11

Secondary decisions

In the event that the first rearranged allele is either non-productive or generates an autoreactive receptor, lymphocytes still have the potential for carrying out secondary rearrangements, and it is interesting to ask whether this takes place with equal probability on both alleles, or whether the initially rearranged early replicating allele is the preferred substrate. Earlier studies had suggested that autoreactive B cells are edited primarily by deletional recombination [64, 65]. However, in

Monoallelic expression at other loci

The olfactory receptor genes make up a large class of sequences that appear to be regulated in a manner similar to that of the immune receptor loci. About 1000 of these genes are distributed amongst distinct clusters spread over almost all of the chromosomes in both man and mouse. The expression of these genes in olfactory neurons is subject to a process of single gene selection that involves clear-cut allelic exclusion, resulting in the appearance of only one receptor per cell [3]. Although

Widespread monoallelic expression

It was always assumed that almost all genes in diploid organisms are expressed biallelically, but two recent studies using genome wide approaches have challenged this concept by showing that between 1 and 5% of autosomal genes in both human and mouse are actually subject to various forms of random monoallelic expression [72•, 73••]. A relatively large fraction of these newly identified genes encode cell-surface proteins, suggesting that monoallelic expression may play a prominent role in

Conclusions

Even though it has been known for a long time that productive rearrangement in the immune system occurs on only one of the two alleles that make up each antigen receptor locus, the mechanisms involved in this process have not yet been fully elucidated. Earlier results had suggested that both alleles may be equally accessible in target B or T cells, and the choice is made stochastically by random hits of the recombination machinery. More recent studies, however, demonstrate that recombination is

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by grants from the Israel Academy of Science (Y.B. and H.C.), Philip Morris USA Inc. and Philip Morris International (Y.B. and H.C.), the National Institutes of Health (Y.B. and H.C.) and the Israel Cancer Research Fund (Y.B. and H.C.).

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