Activation and Inactivation of Immunoglubulin VH Genes

免疫球蛋白 VH 基因的激活和失活

• 批准号: 6464767
• 负责人: RANJAN SEN
• 金额: $ 33.79万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6464767
• 关键词: biological signal transduction; chromatin; gene induction /repression; gene rearrangement; immunoglobulin genes; laboratory mouse; protein tyrosine kinase; transcription factor

DESCRIPTION (provided by the applicant): Assembly of immunoglobulin heavy chain (IgH) genes during B cell differentiation requires two recombination events. First, one of several DH gene segments rearrange to JH gene segments to produce DJH joins. Second, one of several hundred VH gene segments rearrange to the DJH join to produce V(D)J recombined alleles. A small proportion of V(D)J recombined alleles will encode IgH protein. Those cells that make IgH protein will terminate recombination of the IgH gene, a process referred to as allelic exclusion. Earlier studies indicate that allelic exclusion operates at the step of VH to DJH recombination. The mechanism by which VH recombination is stopped is not known. In recent studies of the chromatin structure of the IgH locus we found that VH genes are activated by three distinct mechanisms. The largest VH J558 gene family, that is at the 5' end of the locus, is activated by IL-7. The 3' -most VHS, represented by VH8 1X and VHSM7, are activated only in cells that contain DJH recombined alleles. Genes that lie between VHJ558 and VHSM7, represented by VH10, are activated in V-abl transformed cells suggesting that they may be activated by tyrosine kinases. In this application we propose to rigorously establish mechanisms that activate the intermediate and 3?-VH genes (Aim 1). We then propose to test the model that allelic exclusion is a consequence of terminating signals that activate VH genes (Aim 2). This will be accomplished by a combination of in-vitro and in-vivo analyses in genetically altered mouse strains. These studies are important not only for a comprehensive understanding of IgH gene assembly, but also for insights into the more general question of how large segments of the genome are activated.

描述（由申请人提供）：免疫球蛋白重链的组装 （IGH）B细胞分化过程中的基因需要两个重组事件。 首先，几个DH基因段之一将重新排列到JH基因段生产 DJH加入。第二，几百VH基因段之一重新排列到DJH 加入以产生V（d）J重组等位基因。 v（d）j的一小部分 重组等位基因将编码IGH蛋白。那些生产IGH蛋白的细胞 将终止IGH基因的重组，该过程称为等位基因 排除。较早的研究表明，等位基因排除在步骤中运行 VH重组的VH。停止VH重组的机制 不知道。 在有关IGH基因座的染色质结构的最新研究中，我们发现VH 基因被三种不同的机制激活。最大的VH J558基因 家族在该基因座的5'末端被IL-7激活。 3' - 最多 由VH8 1X和VHSM7代表的VHS仅在包含的单元中激活 DJH重组等位基因。位于VHJ558和VHSM7之间的基因，由 VH10在V-ABL转化的细胞中被激活，表明它们可能是 被酪氨酸激酶激活。 在此应用中，我们建议严格建立激活的机制 中间和3？-VH基因（AIM 1）。然后，我们建议测试模型 等位基因排除是终止激活VH信号的结果 基因（目标2）。这将通过体外和 体内分析遗传改变的小鼠菌株。 这些研究不仅对于对IGH的全面理解很重要 基因组装，也可以洞悉更普遍的问题 基因组的大段被激活。