RNA Processing Regulation of Immunoglobulin Gene Expression

人类基因组被发现编码的基因数量少得令人惊讶。 然而，多达60%的基因可以被替代地加工以产生更大多样性的蛋白质。 因此，为了充分了解基因表达，必须了解替代RNA加工的复杂过程是如何调节的。 这将需要使用完善的规范加工模型来破译这些过程的机械细节。 小鼠免疫球蛋白mu基因作为B淋巴细胞发育过程中调控RNA加工的模型系统已被研究多年。 该基因含有一个与剪接反应竞争的裂解-聚腺苷酸化位点;随着B细胞成熟为浆细胞，这两种加工选择的相对使用受到调节。 在IG mu前体mRNA中RNA加工信号的排列和相对强度比基因特异性顺式作用调控序列对RNA加工的调控更重要。 这表明B细胞和浆细胞之间的调节必须涉及一般RNA加工机制的组分的变化。 已经显示，随着B细胞成熟为浆细胞，裂解-多聚腺苷酸化和剪接活性都发生变化。 此外，RNA代谢的其他步骤，包括转录延伸，核：细胞质mRNA运输和RNA稳定性已被证明是不同的B细胞和浆细胞之间。 该项目的目标是确定参与调节替代IG μ mRNA加工的蛋白质，以更好地理解这种调节机制。 大量证据表明，B细胞的终末分化程序，包括mu-s/mu-m mRNA加工的变化，是由转录调节因子的复杂相互作用驱动的。 微阵列筛选将用于鉴定在B细胞向浆细胞的发育过渡期间表达变化的基因;这些差异表达的基因中的一些将编码与RNA加工调节相关的产物。 候选蛋白的过表达和抑制将决定它们在B细胞成熟期间RNA代谢中的作用。 这项研究将涉及研究生，本科生，并可能，高中学生。

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.