RNA Processing Regulation of Immunoglobulin Gene Expression

免疫球蛋白基因表达的 RNA 加工调控

• 批准号: 0318047
• 负责人: Martha Peterson
• 金额: $ 46.3万
• 依托单位: University of Kentucky Research Foundation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0318047&HistoricalAwards=false
• 关键词: RNA; Processing; Regulation; Immunoglobulin; Gene

The human genome has been found to encode a surprisingly small number of genes. However, as many as 60% of all genes may be alternatively processed to generate a much greater diversity of proteins. Thus, to fully understand gene expression, how the complex process of alternative RNA processing is regulated must be understood. This will require that well-established models for regulated processing be used to decipher the mechanistic details of these processes. The mouse immunoglobulin mu gene has been studied for many years as a model system for regulated RNA processing during B lymphocyte development. This gene contains a cleavage-polyadenylation site that is in competition with a splice reaction; the relative use of these two processing options is modulated as B cells mature to plasma cells. The arrangement and relative strengths of RNA processing signals in the Ig mu pre-mRNA is more important than gene-specific cis-acting regulatory sequences for the RNA processing regulation. This indicates that the regulation between B cells and plasma cells must involve changes in components of the general RNA processing machinery. Both cleavage-polyadenylation and splicing activity have been shown to change as B cells mature to plasma cells. In addition, other steps of RNA metabolism, including transcriptional elongation, nuclear:cytoplasmic mRNA transport and RNA stability have been shown to differ between B cells and plasma cells. The goal of this project is to identify proteins involved in regulating alternative Ig mu mRNA processing to better understand this regulatory mechanism. There is substantial evidence that the terminal differentiation program of B cells, including changes in mu-s/mu-m mRNA processing, is driven by a complex interplay of transcriptional regulators. Microarray screening will be used to identify genes whose expression changes during the developmental transition of B cells to plasma cells; some of these differentially expressed genes will encode products relevant to RNA processing regulation. Over-expression and inhibition of candidate proteins will determine their role in RNA metabolism during B cell maturation. This research will involve graduate, undergraduate, and, potentially, high school students.

已经发现人基因组编码了令人惊讶的少数基因。 但是，所有基因中多达60％的人可能会被处理以产生更大的蛋白质多样性。 因此，为了充分理解基因表达，必须理解如何调节替代RNA处理的复杂过程。 这将要求使用良好的管制处理模型来破译这些过程的机械细节。 多年来，已经研究了多年来研究小鼠免疫球蛋白MU基因，作为在B淋巴细胞发育过程中调节RNA处理的模型系统。 该基因包含一个裂解 - 丙二基化位点，与剪接反应竞争。这两个处理选项的相对使用被调制为成熟到浆细胞的B细胞。 Ig Mu前MRNA中RNA处理信号的排列和相对强度比用于RNA加工调控的基因特异性顺式作用调节序列更为重要。 这表明B细胞和浆细胞之间的调节必须涉及一般RNA加工机械组件的变化。 裂解 - 聚丙烯基化和剪接活性都显示为B细胞成熟到浆细胞。 此外，RNA代谢的其他步骤，包括转录伸长，核：细胞质mRNA转运和RNA稳定性，已证明在B细胞和浆细胞之间有所不同。 该项目的目的是确定与调节替代Ig Mu mRNA处理有关的蛋白质，以更好地了解这种调节机制。 有大量证据表明，B细胞的末端分化程序，包括MU-S/MU-M mRNA处理的变化，是由转录调节剂的复杂相互作用驱动的。 微阵列筛选将用于鉴定其在B细胞发育过渡到浆细胞期间的表达变化的基因。这些差异表达的基因中的一些将编码与RNA处理调控相关的产品。 过表达和抑制候选蛋白将决定它们在B细胞成熟过程中RNA代谢中的作用。 这项研究将涉及毕业生，本科生以及可能是高中生。