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A stepwise epigenetic process controls immunoglobulin allelic exclusion

Key Points

  • The immune-receptor loci are opened up and made accessible to the recombination machinery through a stepwise process that removes sequential layers of gene-repression mechanisms.

  • This process involves changes in replication timing, nuclear positioning, histone modification, heterochromatization and DNA methylation.

  • Allelic exclusion is mediated by a mechanism that is initiated in the early embryo when the two alleles become asynchronously replicating.

  • During B-cell development, one immunoglobulin light-chain (IgL) allele in each cell is packaged in an open nucleosome structure, which is characterized by histone acetylation, whereas the other is kept inaccessible by being heterochromatized.

  • DNA demethylation occurs preferentially on the acetylated IgL κ-allele, and this renders the locus accessible for primary recombination and, if required, secondary editing events.

  • In the absence of functional immunoglobulin, the second locus can still undergo epigenetic opening and become a substrate for recombination.

  • Monoallelic selection is characteristic of other multi-gene systems and might function as the basis for gene diversity in other systems.

Abstract

During the differentiation of T and B cells, immune-receptor loci in the genome must be made sterically accessible so that they can undergo rearrangement. Here, we discuss how this is carried out by the stepwise removal of epigenetic repression mechanisms — such as later-replication timing, heterochromatization, histone hypo-acetylation and DNA methylation — in a manner that initially favours one allele in each cell. We propose that this mechanism of allelic exclusion might also be the basis for the generation of gene diversity in other systems.

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Figure 1: Control of rearrangement through chromatin accessibility.
Figure 2: κ-gene epigenetics.
Figure 3: A model for receptor editing and feedback.

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Acknowledgements

Y.B. and H.C. are supported by research grants from the Israel Academy of Sciences and Humanities, and the National Institutes of Health, United States. Y.B. is also supported by the Fifth European Community Framework Programme on Quality of Life and Management of Living Resources. H.C. is also supported by the Israel Cancer Research Fund.

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Correspondence to Howard Cedar.

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DATABASES

Entrez Gene

ATM

BRG1

H2AX

heterochromatin protein 1

Ikaros

IL-7

p53

PAX5

RAG

SYK

TDT

VpreB

ZAP70

Glossary

EPIGENETIC

Any heritable influence on the function of a chromosome or gene that is not caused by a change in DNA sequence.

V(D)J RECOMBINATION

Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both T-cell and B-cell receptors.

RECOMBINATION SIGNAL SEQUENCE

(RSS). Conserved elements that constitute recognition sites for the V(D)J recombinase proteins, which are encoded by the genes recombination-activating gene 1 (RAG1) and RAG2. They consist of a palindromic heptamer that is immediately adjacent to the coding gene segments — V (variable), D (diversity) or J (joining) — and is separated from a relatively conserved nonamer by a 12- or 23-base-pair spacer.

RECOMBINATION-ACTIVATING GENE (RAG) PROTEINS

RAG proteins are involved in creating the double-stranded DNA breaks that are required to produce the rearranged gene segments encoding the complete protein chains of T-cell and B-cell receptors.

HETEROCHROMATIN

A cytologically defined genomic component that contains repetitive DNA, transposable elements, a ribosomal DNA gene cluster and several protein-encoding genes.

GERMLINE TRANSCRIPTION

Transcription of unrearranged antigen-receptor gene loci that begins before or is coincident with their activation. It is not thought to produce functional protein, and the promoter and initiation sites are often lost in the subsequent rearrangement events.

FLUORESCENCE IN SITU HYBRIDIZATION

(FISH). The use of fluorescent probes to visually label specific DNA sequences in the nuclei of cells that are in the interphase or metaphase stages of mitosis.

CpG ISLANDS

Sequences of 0.5–2 kilobase pairs that are rich in CpG dinucleotides. They are mostly located upstream of housekeeping genes and also of some tissue-specific genes. They are constitutively non-methylated in all animal cell types.

RECEPTOR EDITING

A molecular process that involves secondary rearrangements (mostly of the immunoglobulin light chains) that replace existing immunoglobulin molecules and generate a new antigen receptor with altered specificity.

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Bergman, Y., Cedar, H. A stepwise epigenetic process controls immunoglobulin allelic exclusion. Nat Rev Immunol 4, 753–761 (2004). https://doi.org/10.1038/nri1458

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