Modeling transcriptional and post-transcriptional systems for regulating non-genetic heterogeneity in mammalian cells

项目摘要 实验技术的最新进展允许定量和系统范围内的测量， 哺乳动物细胞的遗传异质性，这是干细胞动力学的关键因素， 分化潜能以及癌细胞的耐药性。然而， 我理解许多关于这种异质性的令人困惑的观察结果， 监管网络。例如，祖细胞在几天的时间尺度上恢复其异质性， 具有极端基因表达模式的亚群，这些细胞从可塑性 在分化过程中，上皮细胞可以是稳定的定型和模式形成的动力学; 在接收信号后，在上皮-间充质光谱中以稳定的连续体分布， 肿瘤的现有的理论对这些重要的动态和模式提供了非常有限的见解。我们 建议将联合收割机数学建模、分析基因调控网络的新方法和 基因表达数据和运动神经元分化系统中的实验，以及涉及 上皮间质转化研究转录和转录后机制 哺乳动物细胞中潜在的非遗传异质性。 我们提出了一个新的理论框架，即用发散振荡器控制祖细胞 动力学与计算方法和实验系统。我们将严格制定和 测试一个新的假设，即在运动神经元分化中振荡器到开关的转变， 发育中的脊髓源于我们最近关于令人惊讶的转录后机制的结果 对于多稳定性和振荡，我们将使用新的代数方法来建立关系 microRNA结合位点的数量和生物学上合理的细胞状态之间的关系。我们将测试 microRNA结合在上皮细胞可塑性实验中的作用。我们将研究 上皮可塑性和microRNAs在肺癌细胞动力学中的作用。拟议研究的成功 将为解释和理解动力学基因提供新的理论基础和新的方法 哺乳动物细胞中非遗传异质性的表达数据。这些理论和方法可以作为 该基金会致力于开发与发育、组织退化和癌症有关的疾病的治疗方法。

PROJECT SUMMARY Recent advances of experimental techniques allow quantitative and systems‐wide measurements of non‐ genetic heterogeneity of mammalian cells, which serves as a crucial factor for stem cell dynamics and differentiation potentials, as well as drug resistance of cancer cells. However, it remains challenging to understand many puzzling observations regarding this type of heterogeneity in terms of underlying gene regulatory networks. For example, progenitor cells restore their heterogeneity on timescales of days from subpopulation with extreme gene expression patterns, and these cells switch from plasticity‐enabling dynamics to robust commitment and pattern formation during differentiation; epithelial cells can be distributed in a stable continuum in the epithelial‐mesenchymal spectrum upon receiving signals in tumors. Existing theories provide very limited insights into these important dynamics and patterns. We propose to combine mathematical modeling, new methods of analyzing gene regulatory networks and gene expression data, and experiments in a motor neuron differentiation system, and systems involving epithelial‐mesenchymal transition to study transcriptional and post‐transcriptional mechanisms underlying non‐genetic heterogeneity in mammalian cells. We propose to test a novel theoretical framework of a diverging oscillator for controlling progenitor cell dynamics with both computational methods and experimental systems. We will rigorously formulate and test a new hypothesis of an oscillator‐to‐switch transition for motor neuron differentiation in the developing spinal cord. Stemming from our recent results on surprising post‐transcriptional mechanisms for multistability and oscillation, we will use novel algebraic approaches to establish the relationship between the number of microRNA bindings sites and biologically plausible cell states. We will test the roles of microRNA binding in epithelial cell plasticity experimentally. We will examine the roles of epithelial plasticity and microRNAs in dynamics of lung cancer cells. The success of the proposed study will provide a new theoretical basis and new methods for interpreting and understanding dynamical gene expression data on non‐genetic heterogeneity in mammalian cells. The theories and methods can used as a foundation to develop therapeutics for diseases related to development, tissue degeneration and cancer.