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Elucidation of the epigenetic regulation of the antigen receptor gene rearrangement

阐明抗原受体基因重排的表观遗传调控

基本信息

批准号：
17590246
负责人：
AGATA Yasutoshi
金额：
$ 2.3万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590246/
关键词：
gene genome regulation of expression development differentiation immunology

项目摘要

1)Analysis of the factors involved in chromatin structural changes induced by E2AWhen E2A was ectopically expressed with RAG1/2 in BOSC 23 cells that are highly efficient in transfection, germline transcription as well as rearrangement were induced in the endogenous immunoglobulin κ locus. E2A was found to associate with the recombination target regions and increase acetylation of histone H3 and H4. Among several histone acetyltransferases examined, p300/CBP were specifically recruited to the target sites by E2A. Consistent with this, overexpression of p300/CBP together with E2A resulted in increased histone acetylation, germline transcription and rearrangement. Conversely, down-regulation of endogenous p300/CBP by siRNA led to reduction of histone acetylation, germline transcription and rearrangement. Based on these observations, E2A was found to recruit p300/CBP to the recombination target regions and induce rearrangement by opening the chromatin structure through the increase of his … More tone acetylation.2)Analysis of the nuclear mechanisms and physiological roles for allelic exclusionAllelic exclusion of the antigen receptor genes is a phenomenon, in which a productive rearrangement takes place only on one allelic chromosome, and ensures that an individual lymphocyte expresses only one antigen receptor. It has been postulated for the possible mechanism underlying allelic exclusion that, once a productive rearrangement has been generated, a negative feedback signal mediated by the antigen receptor prevents continued rearrangement. We found that E2A promotes T cell receptor β gene rearrangement by directly binding to target gene segments to increase chromatin accessibility in a dosage-sensitive manner. Feedback signaling abrogates E2A binding, leading to a decline in accessibility. Conversely, enforced expression of E2A induces rearrangement by overriding the feedback inhibition. Thus, the abundance of E2A is rate limiting in locus activation, and feedback signaling down-regulates E2A activity to ensure allelic exclusion. Less

1)E2 A诱导染色质结构改变的相关因素分析当E2 A与RAG 1/2在高效转染的BOSC 23细胞中异位表达时，内源性免疫球蛋白κ基因座发生了胚系转录和重排。发现E2 A与重组靶区域相关并增加组蛋白H3和H4的乙酰化。在几个组蛋白乙酰转移酶检查，p300/CBP特异性募集到E2 A的靶位点。与此一致，p300/CBP与E2 A一起过表达导致组蛋白乙酰化、生殖系转录和重排增加。相反，通过siRNA下调内源性p300/CBP导致组蛋白乙酰化、生殖细胞转录和重排的减少。基于这些观察结果，发现E2 A将p300/CBP募集到重组靶区域，并通过增加His-1的表达打开染色质结构来诱导重排。 ...更多信息音调乙酰化。2）等位基因排斥的核机制和生理作用的分析抗原受体基因的等位基因排斥是一种现象，其中生产性重排仅发生在一个等位基因染色体上，并确保单个淋巴细胞仅表达一种抗原受体。对于等位基因排斥的潜在可能机制，已经假设一旦产生了生产性重排，由抗原受体介导的负反馈信号阻止继续重排。我们发现E2 A通过直接结合靶基因片段以剂量敏感的方式促进T细胞受体β基因重排，从而增加染色质可及性。反馈信号消除E2 A结合，导致可及性下降。相反，E2 A的强制表达通过超越反馈抑制诱导重排。因此，E2 A的丰度是基因座激活的速率限制，并且反馈信号传导下调E2 A活性以确保等位基因排除。少