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背后的物理原理。从历史上看，遗传学的中心教条认为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戏剧性的变化。这种表观遗传调控的概念代表了我们思考遗传特征的方式的范式变化。在推力1中，PI将开发一个理论模型来解决染色质分离为转录活跃的异染色质和转录沉默的常染色质的问题。在推力2中，PI将对酿酒酵母和裂殖酵母中染色体DNA的重组动力学进行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，该模型基于与控制染色体组织的蛋白质的合作相互作用，捕获维持和放大表观遗传密码的蛋白质的功能。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节机制的前所未有的物理理解水平。国际癌症协会的外展工作包括建立LABScI计划，该计划为正在接受儿童癌症治疗的高中生的教育开发和实施教学模块。未来的推广工作旨在进一步将该项目作为医院-学校教育的普通实验室科学课程在全国范围内推广。该项目由物理系的生命系统物理学项目和分子和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.