Abstract
The recombination-activating genes (RAG-1 and RAG-2) encode a V(D)J recombinase responsible for rearrangements of antigen-receptor genes during T and B cell development, and RAG expression is known to correlate strictly with the process of rearrangement. In contrast to RAG-1, the expression of RAG-2 was not previously detected during any other stage of lymphopoiesis or in any other normal tissue. Here we report that the CpG island-associated promoter of the NWC gene (the third evolutionarily conserved gene in the RAG locus), which is located in the second intron of RAG-2, has bidirectional activity and is responsible for the detectable transcription of RAG-2 in some non-lymphoid tissues. We also identify evolutionarily conserved promoter fragments responsible for this bidirectional activity, and show that it is activated by transcription factor ZFP143. The possible implications of our findings are briefly discussed.
Highlights
Recombination-activating gene 1 (RAG-1) and RAG-2 are closely linked genes encoding two subunits of the lymphocytespecific RAG recombinase, which is indispensable for the V(D)J recombination responsible for the diversity of immunoglobulins (Igs) and T cell receptors (TCRs) [1,2,3,4,5]
The CpG island associated with the NWC promoter becomes methylated, the promoter is inactivated, and its function is taken over by the RAG-1 promoter, which results in expression of hybrid RAG-1/NWC transcripts containing the first exon of the RAG-1 gene [15]
The transcription start site (TSS) of the NWC gene and the beginning of the third exon of RAG-2 are separated by 313 nucleotides (Fig. 1)
Summary
Recombination-activating gene 1 (RAG-1) and RAG-2 are closely linked genes encoding two subunits of the lymphocytespecific RAG recombinase, which is indispensable for the V(D)J recombination responsible for the diversity of immunoglobulins (Igs) and T cell receptors (TCRs) [1,2,3,4,5]. The NWC promoter is linked to an evolutionarily conserved CpG island and is active in non-lymphoid cells, where it drives constitutive expression of NWC [16]. The structure (GC-rich, CpG island-containing, TATA-less) and localization of the primary NWC promoter are typical for bidirectional promoters [18], suggesting that it may be responsible for the transcription of both NWC and RAG-2. We tested this possibility, and report for the first time that the NWC promoter has bidirectional activity, driving detectable expression of RAG-2 in non-lymphoid tissues. We identify two promoter elements capable of binding transcription factor ZFP143 and show that it activates the promoter
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