Mechanisms regulating the target specificity of gene rearrangements in immune system

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Experiments on the class switch recombination of Ig H chain, in which the regional chromatin status and specific regulation of each gene are able to be reproduced in vitro, and on the regulation of AID gene expression, which is essential for Ig class switch recombination were mainly done. It is shown that the chromatin region of target is opened for the recombination using the level of histone acetylation at the region as the general indicator of chromatin status.By adding HDAC inhibitor together with the repression signal for the germline transcription, the hyper-acetylation status of the target region chromatin could be maintained. Even though the target chromatin was kept open in such away, it was not able to make it the target for the recombination. This result indicates that the germline transcription occurring prior to the recombination is not simply the result of the chromatin opening but it directly involved in the process and therefore essential to make the gene the target. Moreover, results suggesting that the release from specific transcriptional repression occurs in B lymphocyte during the activation of AID gene expression were also obtained.In addition, the oligonucleotide containing CpG array was found to repress the class switch recombination to IgG1 and IgE through the repression of germline transcription. The molecular mechanism for this was analyzed by using B lymphocytes from knockout mice of the genes that might be involved in this repression. The results indicate that Id2 and Bcl6 that repress E2A and STAT6 respectively are not involved in this process, but it is mediated by the signals through NFκB and IRF4.