A cis element in the recombination activating gene locus regulates gene expression by counteracting a distant silencer

Yannoutsos, Nikos; Barreto, Vasco M.; Misulovin, Ziva; Gazumyan, Anna; Yu, Wong; Rajewsky, Nikolaus; Peixoto, B. R.; Eisenreich, Thomas; Nussenzweig, Michel C.

doi:10.1038/ni1053

Cited by 73 publications

(74 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL-6 may activate factors that trigger the transcription of RAG genes (47), or it may give rise to factors that push cis elements into counteracting the silencer that normally represses RAG gene transcription (48). More likely, IL-6 may increase the expression level of BR-3, as was recently demonstrated in cytokine-stimulated B cells (49), or it may help to reduce receptor numbers occupied by soluble BAFF to favor transmembrane BAFF engagement (50).…”

Section: Discussionmentioning

confidence: 95%

Transmembrane BAFF from rheumatoid synoviocytes requires interleukin‐6 to induce the expression of recombination‐activating gene in B lymphocytes

Rochas¹,

Hillion²,

Saraux³

et al. 2009

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 95%

Transmembrane BAFF from rheumatoid synoviocytes requires interleukin‐6 to induce the expression of recombination‐activating gene in B lymphocytes

Rochas¹,

Hillion²,

Saraux³

et al. 2009

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…Three distal elements involved in regulation of RAG genes were also identified and found to be located within 22 kbp of the 5 0 end of RAG2 [15,16]. In addition, a silencer located in the intergenic region between RAG1 and RAG2 and an anti-silencer located between 71 and 86 kbp 5 0 of RAG2 were recently described [17].…”

Section: Introductionmentioning

confidence: 99%

“…It is juxtaposed to the 3 0 end of RAG1 andin the mouse and other species relatively well represented in databases, like human and chimpanzee -has its 5 0 untranslated region in the intron of RAG2. In the From the left to the right they are: anti-silencer [17], Erag [16], D3 [15], an element located 2 kbp 5 0 of RAG2 [15] and a silencer [17]. The positions of the primers used in this study are indicated by dotted horizontal arrows.…”

Section: Identification Of Nwc a Third Gene Within The Rag Locusmentioning

confidence: 99%

Identification of a third evolutionarily conserved gene within theRAG locus and itsRAG1-dependent and -independent regulation

2005

View full text Add to dashboard Cite

Recombination-activating gene (RAG)1 and RAG2 encode T and B lymphocyte-specific endonucleases indispensable for rearrangements of antigen-receptor gene segments but also capable of causing deleterious chromosome rearrangements. The mechanisms regulating RAG expression and repression are not clear. Here we identify NWC, a third evolutionarily conserved gene within the RAG locus, and show that it is ubiquitously expressed, with the notable exception of RAG-nonexpressing immature and mature T and B lymphocytes because in lymphocytes it is regulated by the RAG1 promoter and transcribed as RAG1-NWC hybrid mRNA molecules. We also show that in all other cells NWC is controlled by the RAG2 intragenic promoter, which in immature and mature T and B lymphocytes is silent. The possible implications of these findings for understanding the activation and inactivation of RAG genes in lymphocytes and their repression in other cells are discussed.

show abstract

“…DP thymocytes that have successfully generated an ␣␤ TCR express higher TCR␤ chain levels and are referred to as TCR␤ int DP thymocytes. TCR␤ int DP thymocytes continue to undergo V␣ to J␣ rearrangements until recombinase activating gene (RAG) -1 and -2 expression is terminated by the signals of positive selection (12)(13)(14)(15)(16)(17)(18). Thus, a productive VJ␣ rearrangement that does not encode a TCR␣ chain capable of positive selection could be excised and replaced with a new VJ␣ ( Fig.…”

Section: V(d)j Recombination ͉ Gene Rearrangement ͉ T Cell Repertoirementioning

confidence: 99%

Revision of T cell receptor α chain genes is required for normal T lymphocyte development

Huang

Sleckman

Kanagawa

2005

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

To become mature ␣␤ T cells, developing thymocytes must first assemble a T cell receptor (TCR) ␤ chain gene encoding a TCR␤ chain that forms a pre-TCR. These cells then need to generate a TCR␣ chain gene encoding a TCR␣ chain, which, when paired with the TCR␤ chain, forms a selectable ␣␤ TCR. Newly generated VJ␣ rearrangements that do not encode TCR␣ chains capable of forming selectable ␣␤ TCRs can be excised from the chromosome and replaced with new VJ␣ rearrangements. Such replacement occurs through the process of TCR␣ chain gene revision whereby a V␣ gene segment upstream of the VJ␣ rearrangement is appended to a downstream J␣ gene segment. A multistep, gene-targeting approach was used to generate a modified TCR␣ locus (TCR␣ sJ ) with a limited capacity to undergo revision of TCR␣ chain genes. Thymocytes from mice homozygous for the TCR␣ sJ allele are defective in their ability to generate an ␣␤ TCR. Furthermore, those thymocytes that do generate an ␣␤ TCR have a diminished capacity to be positively selected, and TCR␣ sJ/sJ mice have significantly reduced numbers of mature ␣␤ T cells. Together, these findings demonstrate that normal T cell development relies on the ability of developing thymocytes to revise their TCR␣ chain genes.T he checkpoints imposed on developing T cells mandate that they generate T cell receptor (TCR) ␣ and ␤ chains that form an ␣␤ TCR capable of positive selection (1). TCR ␣ and ␤ chain gene assembly is precisely regulated within the context of normal thymocyte development. TCR␤ chain genes are assembled in CD4 Ϫ ͞CD8 Ϫ [double negative (DN)] thymocytes (2-4). Expression of a TCR␤ chain, as a pre-TCR, results in signals that promote cellular expansion and developmental stage progression to the CD4 ϩ ͞CD8 ϩ [double positive (DP)] stage of thymocyte development (5). Pre-TCR signals also promote TCR␣ chain gene assembly and prohibit further TCR␤ chain gene assembly through the process of allelic exclusion (5-7). Because allelic exclusion prohibits DP thymocytes from generating new TCR␤ chains, these cells must generate TCR␣ chains that form an ␣␤ TCR capable of positive selection if they are to become mature T cells.The genes encoding the TCR␣ chain are intermingled with TCR␦ chain genes in the TCR␣͞␦ locus ( Fig. 1) (8). TCR␣ variable region genes are assembled from V␣ and J␣ gene segments. There are Ϸ100 V␣ gene segments clustered in the 5Ј region of the mouse TCR␣͞␦ locus and 61 J␣ gene segments, spanning Ϸ60 kb, clustered in the 3Ј region of the locus (Fig. 1) (8). The V␣ and J␣ gene segments are oriented such that any rearrangement occurs by deletion, excising the intervening DNA from the chromosome (8).Thymocytes entering the DP compartment from the DN compartment express low TCR␤ chain levels, as the pre-TCR, and are referred to as TCR␤ low DP thymocytes. Initial V␣ rearrangements in these cells are targeted to the most 5Ј J␣ gene segments through the activity of the T early ␣ (TEA) promoter (9). A nonproductive VJ␣ rearrangement could be followed by a VJ␣ rearrangement on the oth...

show abstract

A cis element in the recombination activating gene locus regulates gene expression by counteracting a distant silencer

Cited by 73 publications

References 49 publications

Transmembrane BAFF from rheumatoid synoviocytes requires interleukin‐6 to induce the expression of recombination‐activating gene in B lymphocytes

Transmembrane BAFF from rheumatoid synoviocytes requires interleukin‐6 to induce the expression of recombination‐activating gene in B lymphocytes

Identification of a third evolutionarily conserved gene within theRAG locus and itsRAG1-dependent and -independent regulation

Revision of T cell receptor α chain genes is required for normal T lymphocyte development

Contact Info

Product

Resources

About