CAREER: Uncovering the role of splicing factors in transcriptional regulation

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. 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. 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.