Revealing the Physical Principles Underlying Epigenetic Regulation Using Theory, Simulation, and Experiment

在这个项目中，pi将揭示表观遗传调控的物理原理。从历史上看，遗传学的核心教条认为，DNA序列包含了协调细胞功能的所有信息。然而，组蛋白和DNA修饰改变了基因组DNA的物理包装，导致包装遗传物质的表达发生了巨大变化。这种表观遗传调控的概念代表了我们如何看待遗传特征的范式变化。在推力1中，PI将开发一个理论模型来解决染色质分为转录活性异染色质和转录沉默的常染色质的分离问题。在第二阶段，PI将对酿酒酵母和pombe Schizosaccharomyces进行染色体DNA重组动力学的实验测量和理论建模。在推力3中，PI将建立一个动力学模型，该模型捕捉维持和扩增表观遗传密码的蛋白质的功能，该功能基于与控制染色体组织的蛋白质的合作相互作用。通过将理论和计算模型与实验测量相结合，PI将建立对表观遗传调控机制的前所未有的物理理解水平。PI的推广工作包括建立LABScI项目，该项目为正在接受儿童癌症治疗的高中生开发和实施教学模块。未来的推广工作旨在进一步将该方案扩大到全国，作为医院-学校教育的一般实验室科学课程。该项目由物理系的生命系统物理学项目和分子与细胞生物科学系的分子生物物理学项目共同支持。

In this project, the PIs will reveal the physical principles underlying epigenetic regulation. Historically, the central dogma of genetics asserted that DNA sequence holds all of the information that orchestrates cellular function. However, histone and DNA modifications alter the physical packaging of genomic DNA, resulting in dramatic changes in the expression of the packaged genetic material. This notion of epigenetic regulation represents a paradigm change in how we think about genetic traits. In Thrust 1, the PI will develop a theoretical model to address the segregation of chromatin into transcriptionally active heterochromatin and transcriptionally silent euchromatin. In Thrust 2, the PI will perform experimental measurements and theoretical modeling of the reorganization dynamics of chromosomal DNA within Saccharomyces cerevisiae and Schizosaccharomyces pombe. In Thrust 3, the PI will establish a kinetic model that captures the function of the proteins that maintain and amplify the epigenetic code based on cooperative interactions with the proteins that control chromosomal organization. By combining theoretical and computational modeling with experimental measurements, the PI will establish an unprecedented level of physical understanding of the mechanisms of epigenetic regulation. The PI's outreach efforts include the establishment of the LABScI program, which develops and implements teaching modules for the education of high school students that are being treated for childhood cancer. Future outreach efforts aim to further expand the program nationwide as a general laboratory science curriculum for hospital-school education.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences.