Probing co-transcriptional gene regulatory logics in human transcriptomes

点击翻译按钮获取中文摘要

PROJECT SUMMARY The architecture of mammalian genes enables the production of multiple transcripts by using alternative promoters, alternative termination sites, and differentially spliced exons, which greatly expand the coding capacity of our genomes. We recently discovered that exon splicing can activate cryptic promoters located nearby and that these new promoters often arise near annotated internal exons creating “hybrid” exons that can be used as both first and internal exons in different transcripts. The regulation of these processes has profound impacts on gene expression, and yet the specific mechanisms are poorly understood. Indeed, key gaps in our understanding of co-transcriptional gene regulation include the specific mechanisms and the trans- factors involved in the splicing-dependent regulation of transcription and the roles of spliceosome components. Moreover, since exon splicing influences transcription from the most upstream and nearby promoter, it is unclear how the activation of a new promoter affects the expression of alternative promoters in the same genes. The goal of my lab is to understand the molecular processes underlying the functional coupling between transcription and RNA-processing, aiming to uncover novel mechanisms of gene regulation in important contexts. In this proposal, we will combine genetic, molecular, and genomic techniques with high- throughput computational analyses to address two key aspects of co-transcriptional gene regulation. First, we will focus on how splicing activates transcription from hybrid exons and identify key cis- and trans-factors involved in the splicing-dependent activation of promoters of hybrid exons. Also, we hypothesize that splicing- dependent promoter activation affects transcription from nearby alternative promoters by modulating their chromatin environment. We will then work on how promoter activation modulates transcription from alternative promoters and discern the mechanism behind promoter interference that has profound impacts on gene regulation. Furthermore, we will explore the effects of promoter activation on other promoters nearby during stem cell differentiation to define their contribution to gene regulation and cardiac identity. Our research will result in insights crucial to uncovering the molecular events that cumulatively establish co-transcriptional gene regulatory networks. Ultimately, our findings will lead to the development of new computational tools to predict gene regulatory networks and design molecules to control gene expression with therapeutic benefits.