Regulation of the RAG-1 promoter by the NF-Y transcription factor.

Brown, Stephen; Miranda, Gustavo A.; Galić, Zoran; Hartman, Isamu Z.; Lyon, Christopher J.; Aguilera, Renato J.

doi:10.4049/jimmunol.158.11.5071

Cited by 41 publications

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“…However, all of the reporter constructs used by Punturieri et al ( 79) included only 37 nt of downstream DV101S1 sequence, relative to our major transcription start site, so presumably, this region is unimportant for promoter activity. Several other eukaryotic genes have been found to have regulatory elements within their 5Ј untranslated leader regions including RAG-1 (80). Interestingly, the ϩ12 to ϩ25 region from the DV101S1 promoter is highly homologous to the ϩ11 to ϩ25 region from the RAG-1 promoter (80).…”

Section: Discussionmentioning

confidence: 99%

“…Several other eukaryotic genes have been found to have regulatory elements within their 5Ј untranslated leader regions including RAG-1 (80). Interestingly, the ϩ12 to ϩ25 region from the DV101S1 promoter is highly homologous to the ϩ11 to ϩ25 region from the RAG-1 promoter (80). Thirteen of the DV101S1 nucleotides match the RAG-1 nucleotides, if a 1 base gap is introduced.…”

Section: Discussionmentioning

confidence: 99%

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Regulatory Elements in the Promoter of a MurineTCRD VGene Segment

Kienker

Ghosh

Tucker

1998

The Journal of Immunology

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TCRD V segments rearrange in an ordered fashion during human and murine thymic development. Recombination requires the accessibility of substrate gene segments, and transcriptional enhancers and promoters have been shown to regulate the accessible chromatin configuration. We therefore investigated the regulation of TCRD V rearrangements by characterizing the promoter of the first TCRD V segment to be rearranged, DV101S1, under the influence of its own enhancer. Sequences required for full promoter activity were identified by transient transfections of normal and mutated promoters into a human γδ lymphoma, and necessary elements fall between −86 and +66 nt, relative to the major transcription start site. They include a cAMP responsive element (CRE) at −62, an Ets site at −39, a TATA box at −26, the major transcriptional start site sequence (−8 to −5 and −2 to +11), and a downstream sequence (+12 to +33). Gel shift analyses and in vitro DNase I footprinting showed that nuclear proteins bind to the functionally relevant CRE, Ets, +1 to +10 sequence, and the +17 to +21 sequence. Nuclear proteins also bind to an E box at −52, and GATA-3 binds to a GATA motif at −5, as shown by Ab ablation-supershift experiments, but mutations that abrogated protein binding to these sites failed to affect DV101S1 promoter activity. We conclude that not all protein-binding sites within the DV101S1 minimal promoter are important for enhancer driven TCRD gene transcription. Further, the possibility remains that the GATA and E box sites function in enhancer independent DV101S1 germline transcription.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulatory Elements in the Promoter of a MurineTCRD VGene Segment

Kienker

Ghosh

Tucker

1998

The Journal of Immunology

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Characterization of the proximal enhancer element and transcriptional regulatory factors for murine recombination activating gene‐2

et al. 2005

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Recombination-activating gene (RAG)-1 and RAG-2 are essential for V(D)J recombination and are expressed specifically in lymphoid cells. We previously identified two putative enhancer elements, the proximal and distal enhancers, located at -2.6 and -8 kb, respectively, 5 0 upstream of mouse RAG-2, and characterized the distal enhancer element in detail. In this study, to characterize the proximal enhancer in vitro as well as in vivo, we first defined a 170-bp core enhancer element within the proximal enhancer (Ep) and determined its activity in various cells. Ep conferred enhancer activity only in B-lymphoid cell lines, but not in T-or non-lymphoid cell lines. Analysis of the transgenic mice carrying an EGFP reporter gene linked with Ep revealed that Ep activated the transcription of the reporter gene in bone marrow and spleen, but not in thymus or non-lymphoid tissues. Ep was active in both B220 + IgM -and B220 + IgM + subpopulations in the bone marrow and in the B220 + subpopulation in the spleen. Using electrophoretic mobility shift assays and mutational assays, we found that Ikaros and CCAAT/enhancer binding protein cooperatively bind Ep and function as the transcription factors responsible for B cell-specific enhancer activity. These results demonstrate the role of Ep as a cis-regulatory enhancer element for RAG-2-specific expression in B-lymphoid lineages. IntroductionAssembly of Ig and TCR genes by V(D)J recombination is mediated by the products of recombination-activating gene (RAG)-1 and RAG-2 [1, 2]. RAG proteins act together to recognize recombination signal sequences that flank V, D, and J gene segments and introduce the double-stranded DNA breaks between the recombination signal sequences and the gene segments [3]. The expression of RAG-1 and RAG-2 is restricted to lymphoid cells undergoing V(D)J rearrangement [4, 5]. In the absence of either RAG-1 or RAG-2 gene products, the development of mature lymphocytes is completely abrogated and hence results in severe combined immune deficiency in mouse and human [6][7][8]. In human, missense mutations in either RAG-1 or RAG-2 result in the Omenn syndrome, which is characterized by a poor T lymphocyte repertoire [9].There are two waves of RAG-1 and RAG-2 expression in bone marrow B cell precursors. RAG are expressed first in pro-B cell progenitors undergoing Ig heavy-chain gene rearrangement, and the second expression of RAG is seen during Ig j or k light-chain gene rearrangement occurring in pre-B cells [4,10]. In T cell development, RAG areThe first two authors contributed to this work equally. first expressed in pro-T cells when rearrangement of the TCRb chain gene occurs, and secondary expression of RAG occurs when the TCRa chain loci undergo V-J rearrangement to produce mature T cells [11,12]. The transcription of RAG is regulated at different levels. At the chromatin level, Fuller et al. and we reported that a DNase I-hypersensitive (HS) site was identified in the promoter region of mouse and human RAG-1 only in RAG-expressing lymphocytes [13,14]. We a...

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

2005

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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.

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Regulation of the RAG-1 promoter by the NF-Y transcription factor.

Cited by 41 publications

References 0 publications

Regulatory Elements in the Promoter of a MurineTCRD VGene Segment

Regulatory Elements in the Promoter of a MurineTCRD VGene Segment

Characterization of the proximal enhancer element and transcriptional regulatory factors for murine recombination activating gene‐2

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

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