Regulation of Gene Expression By The Exon Junction Complex

智力价值：基因表达是对储存在DNA中的信息进行解码以产生功能蛋白质或RNA的过程。这一过程分多个步骤进行。首先，DNA序列被转录成RNA。然后，可以剪接RNA以去除非编码内含子序列，并在将其翻译成蛋白质之前将其运输到细胞的特定区域。最后，RNA被降解成核苷酸，以终止其表达。这些阶段中的每一个都可以独立调节，但它们也可以通过揭示RNA分子历史的标记联系在一起。一个这样的标记是外显子连接复合体(EJC)，这是一组四个核心蛋白质，在剪接过程中与RNA分子结合，并识别它们是被剪接的。结合的EJC的存在可以改变RNA的稳定性、定位和翻译。该项目是基于在剪接过程中发现了EJC亚基的一种新功能。MAP蛋白是调节细胞存活、增殖和分化的许多发育信号通路的重要介体。然而，细胞在表达MAP激酶基因方面面临挑战，该基因位于一个抑制染色质区域，具有非常大的内含子，必须拼接起来才能产生蛋白质编码转录本。EJC的三个亚基(Mago、Y14和eIF4AIII)特别需要拼接MAP激酶以及从具有类似功能的其他基因转录的RNA。相反，第四个亚基BTZ对MAP激酶没有影响，但对于神经元RNA结合蛋白Elav的正常表达是必需的。该项目将采用全基因组的方法来确定所有受EJC每个亚单位调控的基因，并确定每个组的共同特征。这一分析很可能揭示该复合体作为一个整体及其个别亚单位的新的分子功能。此外，该项目将研究EJC亚单位的两个潜在的新生物学功能。一组实验将测试BTZ是否通过控制Elav调节选择性剪接的能力来影响突触形成。另一组将测试Mago和Y14是否通过产生小RNA来允许正常产卵，这些小RNA用于防御移动的遗传因素。这一结果将使我们更深入地理解剪接和其他基于RNA的调控模式之间的联系。更广泛的影响：这些研究的结果将发表在科学期刊上，并在科学会议上公布，还将通过特雷斯曼实验室的网站接触到广泛的受众。该项目将为研究生和研究生阶段的个人提供高级培训，本科生和高中生，包括人数不足的少数群体，预计也将在夏季参加。此外，她以前的同事和合作者海伦·辛克博士现在是哈莱姆区的一所中学PS 7的科学教师。国际和平研究所将为Sink博士在PS 7的科学活动提供材料和设备，并将在纽约大学的实验室接待Sink？S博士感兴趣的学生开展与研究相关的小项目。这些外联活动将提高少数民族学生在其教育的早期阶段对科学研究的认识。

Intellectual Merit:Gene expression is the process of decoding the information stored in DNA to produce functional proteins or RNA. This process occurs in multiple steps. First, the DNA sequence is transcribed into RNA. The RNA may then be spliced to remove non-coding intron sequences, and transported to specific regions of the cell, before it is translated into protein. Finally, the RNA is degraded into nucleotides to terminate its expression. Each of these stages can be independently regulated, but they can also be linked by markers that reveal the history of an RNA molecule. One such marker is the exon-junction complex (EJC), a set of four core proteins that bind to RNA molecules during splicing and identify them as having been spliced. The presence of a bound EJC can alter RNA stability, localization and translation. This project is based on the discovery of a novel function for EJC subunits in the splicing process itself. The MAP kinase protein is an important mediator of many developmental signaling pathways that regulate cell survival, proliferation and differentiation. However, the cell faces challenges in expressing the MAP kinase gene, which is located in a repressive chromatin region and has very large introns that must be spliced out to produce the protein-coding transcript. Three subunits of the EJC (Mago, Y14 and eIF4AIII) are specifically required to splice MAP kinase as well as RNAs transcribed from other genes that have similar features. In contrast, the fourth subunit, Btz, has no effect on MAP kinase, but is required for the normal expression of a neuronal RNA-binding protein, Elav. This project will take a genome-wide approach to identify all the genes that are regulated by each subunit of the EJC and to determine the common features of each group. This analysis is likely to reveal new molecular functions for the complex as a whole and for its individual subunits. In addition, the project will investigate two potentially new biological functions for subunits of the EJC. One set of experiments will test whether Btz affects synapse formation by controlling the ability of Elav to regulate alternative splicing. Another set will test whether Mago and Y14 allow normal egg production by generating small RNAs used as a defense mechanism against mobile genetic elements. The results will give us a deeper understanding of the connection between splicing and other modes of RNA-based regulation. Broader impacts:The results of these studies will be published in scientific journals and presented at scientific meetings, and will also reach a broad audience through the Treisman lab web site. The project will provide advanced training to individuals at the graduate and postgraduate levels, and undergraduate students and high school students, including under-represented minorities, are also expected to participate during the summers. In addition, a former colleague and collaborator, Dr. Helen Sink, is now a science teacher at PS 7, a middle school in Harlem. The PI will provide Dr. Sink materials and equipment for scientific activities at PS 7 and will host interested students from Dr. Sink?s classes in the laboratory at NYU to carry out small projects related to the research. These outreach activities will increase awareness of scientific research among minority students at an early stage of their education.