CAREER: Uncovering the role of splicing factors in transcriptional regulation

在从转录开始的复杂的基因表达过程中，RNA经历了一个被称为剪接的选择性编辑过程，其中一些部分被保留，而其他部分被丢弃。转录和剪接在时间和空间上是相互联系的。尽管它们之间存在联系，但控制它们耦合的确切分子机制仍然难以捉摸。本项目将研究剪接对转录调控的反馈机制，重点研究剪接因子U1小核核糖核蛋白颗粒（U1snRNP）的作用。在实验室之外，该计划还将其范围扩大到高中和初中学生和教育工作者，优先考虑西班牙裔人口。通过培养科学好奇心和科学素养，研究人员将提供动手研讨会、实验室实习以及计算生物学和统计学方面的教程。总的来说，该项目不仅有望揭示基因表达调控的新层面，而且还积极有助于培养下一代科学家，促进STEM教育的包容性。转录和剪接是内在耦合的；然而，它们共同调控的分子机制仍然知之甚少。本项目以U1小核核糖核蛋白颗粒（U1snRNP）为中心，旨在揭示剪接到转录调控反馈的作用模式和原理。该研究分为两个主要目的：(i)通过剪接确定u1snrnp依赖性启动子调控的规则；（ii）通过转录物长度调控探索驱动u1snrnp依赖性下游启动子激活的机制。第一个目的是评估u1snrnp介导的启动子调控对5'剪接位点强度和位置的依赖性。在第二个目标中，该项目深入研究了U1snRNP抑制对全局替代启动子使用、染色质结构和启动子方向性的影响。通过揭示U1snRNP在启动子调控中的作用机制，该项目将揭示基因调控的新层面。最终，这个项目的发现将为开发先进的计算工具铺平道路，这些工具能够预测基因调控网络，并设计精确控制基因表达的治疗分子。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

In the intricate process of gene expression, which begins with transcription, RNA undergoes a selective editing process called splicing in which some parts are retained, while others are discarded. Transcription and splicing are linked in time and space. Despite their connection, the exact molecular mechanisms governing their coupling remain elusive. This project will investigate the mechanism underlying the feedback of splicing on transcriptional regulation, focusing on the role of the splicing factor U1 small nuclear ribonucleoprotein particle (U1snRNP). Beyond the lab, this initiative extends its reach to high-school and middle-school students and educators, prioritizing outreach to the Hispanic population. By nurturing scientific curiosity and literacy, the researchers will offer hands-on workshops, lab internships, and tutorials on computational biology and statistics. Overall, this project not only promises to unveil novel layers of gene expression regulation but also actively contributes to cultivating the next generation of scientists, fostering inclusivity in STEM education.Transcription and splicing are intrinsically coupled; however, the molecular mechanisms underlying their co-regulation remains poorly understood. This project, centering on the U1 small nuclear ribonucleoprotein particle (U1snRNP), aims to unveil the modes of action and principles governing the feedback from splicing to transcriptional regulation. The study is structured into two main aims: (i) Determining the rules dictating U1snRNP-dependent promoter regulation through splicing, and (ii) Exploring the mechanisms driving U1snRNP-dependent downstream promoter activation via transcript length regulation. The first aim involves assessing the dependency of U1snRNP-mediated promoter regulation on the strength and location of 5' splice sites. In the second aim, the project delves into the effects of U1snRNP inhibition on global alternative promoter usage, chromatin structure, and promoter directionality. By unraveling the mechanisms behind the role of U1snRNP in promoter regulation, this project will reveal novel layers of gene regulation. Ultimately, the findings of this project will pave the way for the development of advanced computational tools capable of predicting gene regulatory networks and designing therapeutic molecules for precise control of gene expression.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.