Collaborative Research: Modeling the Coupling of Epigenetic and Transcriptional Regulation

拥有相同基因组的细胞表现出不同的表型。为了身体的发育和健康，各种组织中的细胞需要忠实地保持其功能特性，同时对环境提示做出必要的改变。也就是说，细胞需要是表型稳定和可塑性的。细胞通过在转录和表观遗传学上对基因表达进行适当的调控来实现这一需求。转录因子在转录水平上的基因调控已经得到了很好的研究。近年来，通过染色质修饰在表观遗传水平上对基因进行调控已经得到了广泛的研究。然而，表观遗传调控的数量本质在很大程度上仍然难以捉摸，人们对表观遗传调控和转录调控的双重影响知之甚少。该项目将开发表观遗传调控的数学框架，以及表观遗传和转录调控的耦合。通过建模和定量实验测量相结合，这项研究将解决细胞表型稳定性和可塑性的基本问题。这个合作项目将为研究生和本科生提供独特的机会，让他们在数学、物理和生命科学的交汇点上工作。通过暑期实习计划，高中生将有机会体验综合建模/实验研究，这将鼓励他们探索自己的兴趣，在未来追求跨学科的研究生涯。快速积累的证据揭示了表观遗传调控基因表达的关键作用。表观遗传修饰是指由非遗传染色质修饰引起的基因表达的稳定和可遗传的变化。然而，表观遗传调控的数量特性，以及表观遗传调控和转录调控对基因表达的耦合效应，还知之甚少。在这个项目中，研究人员将首先开发一个描述基因表达的表观遗传和转录调控的理论框架，并分析表观遗传动力学和基因转录是如何耦合来控制稳定和可塑性基因活动的。然后，研究人员将专注于一个案例研究，即Rb-E2F途径的表观遗传/转录耦合调控，该途径控制着两种不同的细胞命运之间的转换，即细胞静止和增殖。在模型分析的指导下，研究人员将通过实验确定表观遗传修饰和基因转录之间耦合的迫切需要但尚未解决的功能形式。通过整合统计和化学物理、非线性动力学和实验生物学的方法，该项目将通过转录和表观遗传耦合机制来促进我们对基因表达稳定性和灵活性的理解，并相应地促进我们对细胞命运维持和从静止到增殖的转变的理解。

Cells sharing the same genome exhibit different phenotypes. For the development and health of the body, cells in various tissues need to faithfully maintain their functional properties and meanwhile make necessary changes responding to environmental cues. That is, cells need to be phenotypically stable and plastic. Cells achieve this demand through proper regulation of gene expression, transcriptionally and epigenetically. Gene regulation at the transcriptional level via transcription factors has been well studied. Gene regulation at the epigenetic level via chromatin modifications has been extensively researched recently. Yet, the quantitative nature of epigenetic regulation remains largely elusive, and little is known about the coupled effects of epigenetic and transcriptional regulations. This project will develop a mathematical framework for epigenetic regulation as well as coupled epigenetic and transcriptional regulations. By combining modeling and quantitative experimental measurements, this research will address the fundamental question of cell phenotype stability and plasticity. This collaborative project will provide unique opportunities for graduate and undergraduate students to work at the interface of mathematical, physical, and life sciences. Through a summer internship program, high school students will have opportunities to experience integrated modeling/experimental research, which will encourage them to explore their interests in pursuing cross-disciplinary research careers in the future.Rapidly accumulating evidence has revealed the critical role of epigenetic regulation of gene expression. Epigenetic modifications refer to stable and inheritable changes of gene expression caused by non-genetic chromatin modifications. However, the quantitative properties of epigenetic regulation, and the coupled effects of epigenetic and transcriptional regulation on gene expression, are poorly understood. In this project, the investigators will first develop a theoretical framework describing epigenetic and transcriptional regulations of gene expression, and analyze how epigenetic dynamics and gene transcription are coupled to control stable and plastic gene activities. Investigators will then focus on a case study, the coupled epigenetic/transcriptional regulation of the Rb-E2F pathway that controls the transition between two distinct cell fates, cellular quiescence and proliferation. Guided by modeling analysis, investigators will experimentally determine the highly needed but unresolved function form for the coupling between epigenetic modification and gene transcription. By integrating approaches across statistical and chemical physics, nonlinear dynamics, and experimental biology, this project will advance our understanding of gene expression stability and flexibility via coupled transcriptional and epigenetic mechanisms, and correspondingly, of cell fate maintenance and transition between quiescence and proliferation.