Probing co-transcriptional gene regulatory logics in human transcriptomes

项目总结 哺乳动物基因的结构使其能够通过使用可选的 启动子、替代终止位点和差异剪接外显子，这极大地扩展了编码 我们基因组的容量。我们最近发现外显子剪接可以激活位于 这些新的启动子经常出现在有注释的内部外显子附近，这些外显子产生 在不同的转录本中既可以用作第一外显子，也可以用作内部外显子。对这些过程的监管有 对基因表达有深远的影响，但具体机制却知之甚少。的确，Key 在我们对共转录基因调控的理解中存在的差距包括特定的机制和反式- 参与剪接依赖的转录调控的因子和剪接体组件的作用。 此外，由于外显子剪接影响最上游和附近启动子的转录，因此 不清楚新启动子的激活如何影响同一启动子中可选启动子的表达 基因。我的实验室的目标是了解功能耦合背后的分子过程。 在转录和RNA加工之间，旨在揭示基因调控的新机制 重要的背景。在这项提案中，我们将结合遗传、分子和基因组技术与高度... 吞吐量计算分析，以解决共转录基因调控的两个关键方面。首先，我们 将专注于剪接如何激活杂交外显子的转录，并识别关键的顺式和反式因子 参与依赖剪接的杂交外显子启动子的激活。另外，我们假设拼接- 依赖启动子的激活通过调节附近替代启动子的转录来影响其转录 染色质环境。然后我们将研究启动子的激活是如何调节转录的 启动子和了解启动子干扰背后对基因产生深刻影响的机制 监管。此外，我们还将探讨启动子激活对附近其他启动子的影响 干细胞分化以确定它们对基因调控和心脏特性的贡献。我们的研究将 导致对揭示累积建立共转录基因的分子事件至关重要的洞察 监管网络。最终，我们的发现将导致开发新的计算工具来预测 基因调控网络和设计分子，以控制基因表达的治疗效益。

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.