Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene
| Autor: | Esther Roldan, Abdallah Souabni, Jane A. Skok, Giorgia Salvagiotto, Martin Fuxa, Meinrad Busslinger |
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| Rok vydání: | 2004 |
| Předmět: |
T-Lymphocytes
Locus (genetics) chemical and pharmacologic phenomena Biology Mice immune system diseases hemic and lymphatic diseases Genetics Animals Allele Gene VDJ Recombinases Gene Rearrangement Recombination Genetic B-Lymphocytes Genes Immunoglobulin Reverse Transcriptase Polymerase Chain Reaction V(D)J recombination PAX5 Transcription Factor Gene rearrangement Flow Cytometry Molecular biology Research Papers Chromatin DNA-Binding Proteins Phenotype Organ Specificity Immunoglobulin heavy chain PAX5 Immunoglobulin Heavy Chains Gene Deletion Developmental Biology Transcription Factors |
| Zdroj: | Genesdevelopment. 18(4) |
| ISSN: | 0890-9369 |
| Popis: | The subnuclear location and chromatin state of theimmunoglobulin heavy-chain(IgH) locus have been implicated in the control ofV(D)Jrecombination.VH-to-DJHrearrangement of distal, but not proximalVHgenes, furthermore, depends on the B-lineage commitment factor Pax5 (BSAP). Here we demonstrate that ectopicPax5expression from theIkarospromoter induces proximal rather than distalVH–DJHrearrangements inIkPax5/+thymocytes, thus recapitulating the loss-of-function phenotype ofPax5–/–pro-B cells. The phenotypic similarities of both cell types include (1) chromatin accessibility of distalVHgenes in the absence ofVH–DJHrearrangements, (2) expression of the B-cell-specific regulator EBF, (3) central location ofIgHalleles within the nucleus, and (4) physical separation of distalVHgenes from proximal segments in an extendedIgHlocus. Reconstitution ofPax5expression inPax5–/–pro-B cells induced large-scale contraction and distalVH–DJHrearrangements of theIgHlocus. Hence,VH–DJHrecombination is regulated in two steps during early B-lymphopoiesis. TheIgHlocus is first repositioned from its default location at the nuclear periphery toward the center of the nucleus, which facilitates proximalVH–DJHrecombination. Pax5 subsequently activates locus contraction and distalVH–DJHrearrangements in collaboration with an unknown factor that is present in pro-B cells, but absent in thymocytes. |
| Databáze: | OpenAIRE |
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