REGULATION OF TCRB CHAIN GENE REARRANGEMENT

描述（改编自研究者摘要）：淋巴细胞抗原 受体基因通过位点特异性重组过程组装，称为 作为V（D）J重组，这是严格调控的背景下， 淋巴细胞发育此外，抗原受体链的表达是 适当的淋巴细胞发育阶段进展所需。因此，我们认为， 理解V（D）J重组的机制基础将提供 淋巴细胞发育的分子基础的重要见解。t细胞 受体（TCR）β基因重排是有序的发展过程中， D β到J β重排先于V β到D β重排。 此外，V-β到D-β重排在以下背景下被调节： 等位基因排斥他们已经证明，V-β到D-β重排是 通过D-beta对这一步骤的约束进行机械耦合 重组信号序列（RSS）超过12/23兼容性。的目标 本提案中描述的研究旨在阐明 负责通过5'D-β将V-β偶联到D-β重排， RSS并了解它们在调节TCR β有序组装中的作用 T细胞发育过程中的基因。这将通过三个 明确的目标。1.将进行5'D-β RSS的突变分析， 确定负责V-β与D-β偶联的区域 重排此外，他们将确定是否通过特定的耦合 RSS可推广到其他重排步骤。2.的机制 负责通过5'D-β RSS将V-β重排偶联至D-β重排 将被阐明。他们将确定5'的要求是否 D-β RSS是严格的顺式作用。如果需要反式作用因子， 将试图分离这些因素。转录起始的作用， 从5'D-β RSS中的TATA盒， 将重新安排。3.他们将决定TCR-β 等位基因排除伴随着转录活性的变化， 甲基化和/或染色质结构。此外，本发明还提供了一种方法， V-β到D-β重排偶联在 将评估等位基因排除的效果。

DESCRIPTION (Adapted from the Investigator's abstract): Lymphocyte antigen receptor genes are assembled by a site-specific recombination process, referred to as V(D)J recombination, which is tightly regulated within the context of lymphocyte development. Furthermore, expression of antigen receptor chains is required for appropriate lymphocyte developmental stage progression. Therefore, understanding the mechanistic basis of V(D)J recombination will provide important insights into the molecular basis of lymphocyte development. T-cell receptor (TCR) beta gene rearrangement is ordered during development with D-beta to J-beta rearrangement preceding V-beta to D-beta rearrangement. Furthermore, V-beta to D-beta rearrangement is regulated in the context of allelic exclusion. They have shown that V-beta to D-beta rearrangement is mechanistically coupled through constraints placed on this step by the D-beta recombination signal sequence (RSS) beyond 12/23 compatibility. The goals of the studies described in this proposal are to elucidate the mechanisms responsible for coupling of V-beta to D-beta rearrangement by the 5' D-beta, RSS and to understand their role in regulating the ordered assembly of TCR beta genes during T-cell development. This will be accomplished through three specific aims. 1. Mutational analyses of the 5' D-beta RSS will be conducted to determine the regions responsible for coupling of V-beta to D-beta rearrangement. In addition, they will determine whether coupling by specific RSSs is generalizable to other rearrangement steps. 2. The mechanisms responsible for coupling V-beta to D-beta rearrangement by the 5' D-beta RSS will be elucidated. They will determine whether the requirement for the 5' D-beta RSS is strictly cis-acting. If trans-acting factors are required, they will attempt to isolate these factors. The role of transcriptional initiation, from the TATA box in the 5' D-beta RSS, in coupling V-beta to D-beta rearrangement will be determined. 3. They will determine whether TCR-beta allelic exclusion is accompanied by changes in transcriptional activity, methylation and/or chromatin structure of V-beta gene segments. In addition, the potential mechanistic role of V-beta to D-beta rearrangement coupling in effecting allelic exclusion will be assessed.