URoL: Epigenetics 2: Connecting cell fate and epigenome drift through physical models of chromatin structure and dynamics

URoL：表观遗传学 2：通过染色质结构和动力学的物理模型连接细胞命运和表观基因组漂移

• 批准号: 2022182
• 负责人: Timothy Downing
• 金额: $ 300万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2022182&HistoricalAwards=false
• 关键词: URoL; Epigenetics; Connecting; cell; fate

When cells divide, not only the genetic sequence but also the chemical additions to the DNA and its three-dimensional organization (the so-called epigenome) must be replicated. The epigenome plays a central role in controlling the activity levels of individual genes within a cell, and correct replication is critically important for maintaining cellular function from one cell generation to the next. Through a combination of genomics, microscopy, and computational modeling, this project seeks to uncover the molecular and physical principles of epigenome replication. The results are expected to open new opportunities for cellular engineering. This project will broaden participation in research at the crossroads of molecular biology, applied mathematics, and data-science for high school and undergraduate students, with an emphasis on recruitment and training of students from underrepresented groups. In addition, the project will expand access to science education through a unique program for middle- and high-school students in hospital settings.Temporal variation over the cell cycle is an under-appreciated source of heterogeneity in the epigenetic landscape and an under-utilized mechanism of control in epigenome engineering. This project will characterize how sub-cell cycle dynamics in DNA and histone methylation after replication direct the physical compaction and phase separation of chromatin to ultimately drive both the activation of genes during stem cell differentiation and the divergence of epigenetic patterns observed across multiple cell generations. The project will establish whether temporal heterogeneity in DNA and/or histone methylation operates as a critical feature of mammalian life that either facilitates cell state-transitions, leads to error accumulation and drift in the regulatory landscape of cells, or both. In addition to advancing the fundamental understanding of epigenome regulation and dynamics, the project will deliver: predictive models rooted in polymer physics theory and biomolecular kinetics, which will unify mechanistic principles with ‘omic-scale datasets, and novel tools (biochemical, genetic, and optical) for measuring and perturbing epigenome dynamics, thereby advancing the fields of developmental biology, biotechnology, and biophysics/mathematical biology.This project is funded by the Understanding the Rules of Life: Epigenetics Program, administered as part of NSF's Ten Big Ideas through the Division of Emerging Frontiers in the Directorate for Biological Sciences. Co-funding is provided by the Genetic Mechanisms Program, Division of Molecular and Cellular Biosciences, Directorate for Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

当细胞分裂时，不仅遗传序列，而且DNA的化学添加物及其三维组织（所谓的表观基因组）必须复制。 表观基因组在控制细胞内单个基因的活性水平方面起着核心作用，正确的复制对于从一代细胞到下一代细胞维持细胞功能至关重要。通过基因组学，显微镜和计算建模的结合，该项目旨在揭示表观基因组复制的分子和物理原理。 这些结果有望为细胞工程开辟新的机会。 该项目将扩大高中和本科生对分子生物学、应用数学和数据科学交叉领域研究的参与，重点是招募和培训来自代表性不足群体的学生。此外，该项目将扩大通过一个独特的计划，为初中和高中学生在医院settings.Temporal变化在细胞周期中的科学教育是一个未得到充分重视的异质性来源的表观遗传景观和未充分利用的控制机制在表观基因组工程。该项目将描述复制后DNA和组蛋白甲基化的亚细胞周期动力学如何指导染色质的物理压实和相分离，以最终驱动干细胞分化过程中基因的激活和多代细胞中观察到的表观遗传模式的分歧。该项目将确定DNA和/或组蛋白甲基化的时间异质性是否作为哺乳动物生命的关键特征，促进细胞状态转换，导致细胞调控景观中的错误积累和漂移，或两者兼而有之。除了推进对表观基因组调控和动态的基本理解外，该项目还将提供：基于聚合物物理理论和生物分子动力学的预测模型，将机械原理与“组学规模数据集”和新工具统一起来（生物化学、遗传学和光学）用于测量和扰动表观基因组动力学，从而推进发育生物学，生物技术，该项目由理解生命规则：表观遗传学计划资助，该计划作为NSF十大理念的一部分，通过生物科学理事会新兴前沿部门进行管理。共同资助是由遗传机制计划，分子和细胞生物科学司，生物科学理事会。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。