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E2A and EBF Act in Synergy with the V(D)J Recombinase to Generate a Diverse Immunoglobulin Repertoire in Nonlymphoid Cells

Published on Feb 1, 2000in Molecular Cell14.548
· DOI :10.1016/S1097-2765(00)80429-3
William J. Romanow6
Estimated H-index: 6
(UCSD: University of California, San Diego),
Anton W. Langerak54
Estimated H-index: 54
(EUR: Erasmus University Rotterdam)
+ 4 AuthorsCornelis Murre65
Estimated H-index: 65
(UCSD: University of California, San Diego)
Abstract
Abstract Immunoglobulin (Ig) and T cell receptor (TCR) genes are assembled during lymphocyte maturation through site-specific V(D)J recombination events. Here we show that E2A proteins act in concert with RAG1 and RAG2 to activate Ig Vκ1J but not Igλ VλIII–Jλ1 rearrangement in an embryonic kidney cell line. In contrast, EBF, but not E2A, promotes VλIII–Jλ1 recombination. Either E2A or EBF activate IgH D H 4J recombination but not V(D)J rearrangement. The Ig coding joints are diverse, contain nucleotide deletions, and lack N nucleotide additions. Igκ VJ recombination requires the presence of the E2A transactivation domains. These observations indicate that in nonlymphoid cells a diverse Ig repertoire can be generated by the mere expression of the V(D)J recombinase and a transcriptional regulator.
  • References (47)
  • Citations (213)
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References47
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#1Ralph Klein (LMU: Ludwig Maximilian University of Munich)H-Index: 3
#2Hans G. Zachau (LMU: Ludwig Maximilian University of Munich)H-Index: 51
23 CitationsSource
#1David R. Weaver (Harvard University)H-Index: 80
#2Nikolai V. Boubnov (Harvard University)H-Index: 5
Last. Jane Staunton (Harvard University)H-Index: 6
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9 CitationsSource
#1Mary O'Riordan (UCSF: University of California, San Francisco)H-Index: 3
#2Rudolf Grosschedl (UCSF: University of California, San Francisco)H-Index: 69
288 CitationsSource
#1Amit Golding (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 2
#2Simon ChandlerH-Index: 2
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Lineage specificity and temporal ordering of immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement are reflected in the accessibility of recombination signal sequences (RSSs) within chromatin to in vitro cleavage by the V(D)J recombinase. In this report, we investigated the basis of this regulation by testing the ability of purified RAG1 and RAG2 proteins to initiate cleavage on positioned nucleosomes containing RSS substrates. We found that nicking and double-strand DNA cleavage of R...
139 CitationsSource
#1Mark Eben Massari (UCSD: University of California, San Diego)H-Index: 7
#2Patrick A. Grant (PSU: Pennsylvania State University)H-Index: 36
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Abstract The class I helix-loop-helix (HLH) proteins, which include E2A, HEB, and E2-2, have been shown to be required for lineage-specific gene expression during T and B lymphocyte development. Additionally, the E2A proteins function to regulate V(D)J recombination, possibly by allowing access of variable region segments to the recombination machinery. The mechanisms by which E2A regulates transcription and recombination, however, are largely unknown. Here, we identify a novel motif, LDFS, pres...
130 CitationsSource
#1Tomasz SzczepańskiH-Index: 37
Last. Jacques J.M. van DongenH-Index: 90
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Rearranged IGH genes were detected by Southern blotting in 22% of 118 cases of T-cell acute lymphoblastic leukemia (ALL) and involved monoallelic and biallelic rearrangements in 69% (18/26) and 31% (8/26) of these cases, respectively. IGH gene rearrangements were found in 19% (13/69) of CD3− T-ALL and in 50% of TCRγδ+ T-ALL (12/24), whereas only a single TCRβ+ T-ALL (1/25) displayed a monoallelic IGH gene rearrangement. The association with the T-cell receptor (TCR) phenotype was further suppor...
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A key feature of B and T lymphocyte development is the generation of antigen receptors through the rearrangement and assembly of the germline variable (V), diversity (D), and joining (J) gene segments. However, the mechanisms responsible for regulating developmentally ordered gene rearrangements are largely unknown. Here we show that the E2A gene products are essential for the proper coordinated temporal regulation of V(D)J rearrangements within the T cell receptor (TCR) γ and δ loci. Specifical...
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#1Jongbum Kwon (Harvard University)H-Index: 13
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Abstract B and T cell receptor gene assembly by V(D)J recombination is tightly regulated during lymphoid development. The mechanisms involved in this regulation are poorly understood. Here we show that nucleosomal DNA is refractory to V(D)J cleavage. However, the presence of HMG1, a chromatin-associated nonhistone DNA-binding protein, stimulates V(D)J cleavage of nucleosomal templates. This HMG1 stimulation is differentially affected by the rotational or translational positioning of the recombin...
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The transcription factors encoded by the E2A and early B cell factor ( EBF ) genes are required for the proper development of B lymphocytes. However, the absence of B lineage cells in E2A - and EBF -deficient mice has made it difficult to determine the function or relationship between these proteins. We report the identification of a novel model system in which the role of E2A and EBF in the regulation of multiple B lineage traits can be studied. We found that the conversion of 70Z/3 pre-B lymph...
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Insulin plays an essential role in mammals in the regulation of carbohydrate, protein, and fatty acid metabolism. In adults, insulin is expressed exclusively in pancreatic β cells, the major endocrine cell type in the islet of Langerhans which are distributed throughout the pancreas. A deficiency in the production of insulin causes diabetes mellitus, a complex and debilitating disease that if untreated is eventually fatal. Pancreatic β cell-type-specific transcription of the insulin gene appears...
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Summary Expression of vast repertoires of antigen receptors by lymphocytes, with each cell expressing a single receptor, requires stochastic activation of individual variable (V) genes for transcription and recombination. How this occurs remains unknown. Using single-cell RNA sequencing (scRNA-seq) and allelic variation, we show that individual pre-B cells monoallelically transcribe divergent arrays of Vκ genes, thereby opening stochastic repertoires for subsequent Vκ-Jκ recombination. Transcrip...
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V(D)J recombination occurs during lymphocyte development to generate antigen receptor diversity. This process is important because lymphocytes require a set of receptors that can recognize and respond to a wide variety of foreign antigens as part of the adaptive immune response. There are three immunoglobulin loci and four T cell receptor loci, which are rearranged in developing B and T cells in the bone marrow and thymus, respectively. The mechanism underlying this process and the recombination...
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The Igκ locus, which is spread over 3Mb of genomic DNA and contains >100 variable (V) genes, serves as an important model system to study long-range chromatin interactions. Here, we will discuss how in developing B cells in the bone marrow the accessibility of individual Vκ segments is controlled by many lineage-specific and ubiquitously expressed transcription factors that act on various cis-regulatory elements, including promoters, enhancers, and insulators. This dynamic control furthermore in...
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