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Topic 03

Mathematical Modelling and Analysis of AGO-Mediated Alternative Splicing Regulatory Mechanisms

Alternative splicing is one of the essential mechanisms of gene expression regulation in eukaryotes, allowing a single gene to produce multiple protein isoforms and greatly increasing the diversity of the proteome. AGO proteins, as core components of the RNA-induced silencing complex, play a crucial role in microRNA-mediated gene expression regulation. Growing evidence suggests that AGO proteins also participate in the regulation of alternative splicing, but their specific mechanisms of action remain elusive.

This project aims to investigate the regulatory mechanisms of AGO-mediated alternative splicing through mathematical modelling and computational analysis from the following three aspects:

  1. Interaction network between AGO and other splicing factors: We will integrate protein-protein interaction data and RNA-seq data to construct an interaction network between AGO and other splicing factors (such as SR proteins, hnRNPs, etc.). By employing kinetic models or stochastic process models, we will simulate the competitive binding and dynamic equilibrium of AGO and splicing factors on pre-mRNA, and study how the topological structure and dynamic properties of the AGO-splicing factor interaction network influence the regulation mode and efficiency of alternative splicing.

  2. Mechanistic model of AGO-mediated splicing dynamics: Based on existing experimental evidence and theoretical hypotheses, we will build a mechanistic model of AGO-mediated splicing dynamics. The model can adopt different mathematical forms, such as ordinary differential equations, stochastic processes, or Boolean networks, to describe the interactions and dynamic changes among key components such as AGO, pre-mRNA, and splicing factors. Through model simulations and parameter analysis, we will investigate the dynamic behaviour and regulatory mechanisms of AGO-mediated splicing under different conditions.

  3. Coupling model of AGO-mediated splicing with other gene expression regulation processes: We will consider the kinetic coupling between AGO-mediated splicing and other gene expression regulation processes, such as transcription, mRNA stability, RNA export, etc. We will construct multi-level and multi-scale mathematical models to describe the mutual influence and synergistic effects among different regulatory processes. Through model analysis, we will study the role and status of AGO-mediated splicing in the entire gene expression regulatory network.

This project will comprehensively utilise theoretical tools such as mathematical modelling, dynamic analysis, and statistical inference, and closely integrate with experimental biology to quantitatively reveal the dynamic mechanisms of AGO-mediated alternative splicing regulation and deepen our understanding of its role in gene expression processes. The research findings from this project are expected to provide a theoretical basis for developing new RNA therapeutic strategies and biotechnologies.

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