REGULATION OF IGH MU LOCUS CLASS SWITCH RECOMBINATION

描述(研究人员摘要)：在体液免疫反应中， 免疫球蛋白(Ig)类切换改变了 抗体，在不改变其对抗原的特异性的情况下，通过取代重的 U基因的链恒定区(CH)序列与伽马基因的序列， Epsilon或阿尔法基因。这是通过重组DNA序列来完成的 (S区)5‘的铜和“下游”的CH基因。根据目前的情况 响应于特定B的类切换重组(CSR)的模型、调节 细胞刺激是通过调节细胞的转录活性来实现的 以CH基因为靶点，产生所谓的“生殖系”(或“开关”)转录本。 U轨迹在班级转换中起着特别重要的作用，因为SU是 每一次CSR活动的义务捐赠者。然而，目前的企业社会责任模式 法规不能令人满意地解释企业社会责任活动的所有特征， 由于u位点转换转录本在整个B细胞中表达 在没有可检测到的企业社会责任活动的情况下的发展。此外，删除 已知的U Switch转录本的调控和结构元素有 对美国企业社会责任只有部分影响。在一系列实验中，这些实验源于 观察到，我们最近发现了新的u基因座转录单位 这可能涉及到企业社会责任的监管。充分利用这一新功能 信息，我们在这里提出了一系列实验，旨在阐明 在u点影响企业社会责任的监管机制。具体来说，我们将 描述调控新转录本表达的元件，以及 通过靶向突变来评估它们的功能。为了测试世代和 正如最近提出的那样，u开关转录本的剪接对于CSR是必不可少的 对于其他CH基因，我们将替换整个u开关转录本 带有外源DNA序列的区域。在转基因实验中，我们将分析 顺式和反式调节机制在控制SU中的作用 重组。最后，通过用不同类型的 序列(重复和非重复，是否与S相关)，我们将建立 作为有效CSR的SU区序列的分子要求 底物。

DESCRIPTION (investigator's abstract): During a humoral immune response, immunoglobulin (Ig) class switching changes the effector function of an antibody, without altering its specificity for antigen, by replacing the heavy chain constant region (CH) sequences of the u gene with those of a gamma, epsilon or alpha gene. This is accomplished via recombination of DNA sequences (S regions) 5' of Cu and of the "downstream" CH genes. According to the current model, regulation of class switch recombination (CSR) in response to specific B cell stimuli is achieved by modulation of the transcriptional activity of the target CH genes to generate so-called "germline" (or "switch") transcripts. The u locus plays a particularly important role in class switching, since Su is the obligate donor of every CSR event. Yet, the present models of CSR regulation do not satisfactorily explain all the features of u CSR activity, since the u locus switch transcripts are expressed throughout B cell development in the absence of detectable CSR activity. Moreover, deletions of the known regulatory and structural elements of the u switch transcripts have only a partial effect on u CSR. In a series of experiments stemming from these observations, we have recently identified novel u locus transcription units that may be involved in CSR regulation. Taking advantage of this new information, we propose here a series of experiments aimed at elucidating the regulatory mechanisms that affect CSR at the u locus. Specifically, we will characterize the elements that regulate expression of the new transcripts, and assess their function by targeted mutagenesis. To test whether generation and splicing of u switch transcripts is essential for CSR, as recently suggested for other CH genes, we are going to replace the entire u switch transcript region with exogenous DNA sequences. In transgenic experiments, we will assay for the role of cis- and trans-acting regulatory mechanisms in controlling Su recombination. Finally, by replacing the endogenous Su with different types of sequences (repetitive and non-repetitive, S-related or not) we will establish the molecular requirements for the Su region sequences as efficient CSR substrates.