NIH Research Festival
FARE Award Winner
T and B lymphocytes produce diverse antigen receptors through recombination of variable (V), diversity (D) and joining (J) gene segments at T cell receptor and immunoglobulin loci. Rag1/Rag2 endonuclease initiates V(D)J recombination by introducing double strand breaks. This reaction is tightly regulated to minimize genomic damage by permitting RAG access only to the appropriate antigen receptor locus depending on cell type and developmental stage. In one exception to this rule immunoglobulin heavy chain (IgH) gene rearrangements have been reported in 30-50% of developing T cells. To understand the basis for this unexpected activity, we examined IgH chromatin structure, transcription and recombination in CD4+CD8+ (DP) thymocytes generated by expression of a rearranged TCR beta transgene. We showed that several histone modifications that characterize a fully active locus such as H3K9 acetylation H3K4 trimethylation were reduced in CD4+CD8+ thymocytes compared to pro-B cells. In addition, specific noncoding RNAs and DNAseI hypersensitive sites within the locus were reduced in CD4+CD8+ thymocytes in comparison to pro-B cells, indicative of reduced enhancer activity. Using DNA-FISH we showed that large scale locus contraction of IgH locus was absent in CD4+CD8+ thymocytes. These studies provide the mechanistic basis for incomplete assembly of functional immunoglobulin heavy chains in wrong cell types.
Scientific Focus Area: Immunology
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