Epigenetics of antigen-receptor gene assembly

Abstract

IntroductionIt is established that the temporal and lineage specificity of V(D)J rearrangement is controlled at multiple levels [1,2]. These include germ-line transcription, chromatin remodeling, histone acetylation and DNA methylation. It is, however, unknown how a region spanning large genomic distances allows the assembly of antigen receptor genes. Recent data have suggested that an underlying structural order must exist that facilitates the association of DNA elements separated by large genomic distances. B cell development and ordered immunoglobulin gene rearrangementThe developmental progression of B cells has been characterized on the basis of antigen receptor gene rearrangements and on the dynamic expression patterns of cell surface proteins, which have served as maturation markers [3]. The Igh locus is comprised of distinct DNA elements encoding the variable (V), diversity (D), joining (J), and constant (C) regions. Eight Igh constant regions encode for distinct isotypes that include C μ , C δ , C γ1 C γ2a , C γ2b , C γ3 , C α and C ε . Upstream of the IgM constant region are located twelve D H and four J H segments. Fifteen partially dispersed V region families are present that span approximately 2 Mbp of genomic sequence. The IgK and L light chain loci are also organized into distinct DNA elements, encoding V H , J H and C H segments. Ig V H , D H and J H elements are flanked by recombination signal sequences that interact with the RAG1 and RAG2 gene products.In pro-B cells, Igh D H J H joining precedes that of V H (D H )J H gene rearrangement [4]. Once a V(D)J gene rearrangement leads to a productive joint, pre-BCR signaling acts to inhibit RAG1 and RAG2 gene expression and to promote the survival, expansion and developmental progression of large pre-B cells [5.6]. The expansion phase is followed by cell cycle arrest, during which RAG gene expression is reactivated to initiate the rearrangement of the Ig light chain genes. In the presence of self-reactivity, continued rearrangements will replace primary IgK VJ joints, generating receptors with novel specificities. Once a BCR is expressed which lacks auto-reactivity, tonic signaling mediated by the BCR will permanently suppress RAG1 and RAG2 gene expression. Tonic BCR signaling will also trigger the migration of B cells to the peripheral lymphoid organs where they, upon interacting with pathogens, will undergo class switching and somatic hypermutation. T-lineage development and T cell receptor gene rearrangementT-lineage cells also develop sequentially [7]. Two distinct T cell lineages develop from a common progenitor, named αβ and γδ T cells. The rearrangement of the TCRβ and γδ loci is Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production...

Choreography of Ig allelic exclusion

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Poised Transcription Factories Prime Silent uPA Gene Prior to Activation

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