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

当细胞分裂时，不仅基因序列，而且DNA及其三维组织（所谓的表观基因组）的化学添加物也必须被复制。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，正确的复制对于维持细胞一代到下一代的细胞功能至关重要。通过基因组学、显微镜和计算模型的结合，该项目旨在揭示表观基因组复制的分子和物理原理。这一结果有望为细胞工程开辟新的机会。该项目将扩大高中生和本科生在分子生物学、应用数学和数据科学交叉领域的研究参与，重点是招募和培训来自代表性不足群体的学生。此外，该项目还将通过一个独特的方案，为医院环境中的初中生和高中生扩大接受科学教育的机会。细胞周期的时间变化是表观遗传景观异质性的一个未被充分认识的来源，也是表观基因组工程中未被充分利用的控制机制。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，最终驱动干细胞分化过程中基因的激活和在多代细胞中观察到的表观遗传模式的差异。该项目将确定DNA和/或组蛋白甲基化的时间异质性是否是哺乳动物生命的一个关键特征，它要么促进细胞状态转变，要么导致细胞调控环境中的错误积累和漂移，或者两者兼而有之。除了推进对表观基因组调控和动力学的基本理解之外，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，这将统一机制原理与基因组尺度数据集，以及用于测量和扰动表观基因组动力学的新工具（生物化学，遗传和光学），从而推进发育生物学，生物技术和生物物理学/数学生物学领域。该项目由理解生命规则：表观遗传学项目资助，该项目由生物科学理事会新兴前沿部门管理，是NSF十大理念的一部分。由生物科学理事会分子和细胞生物科学部遗传机制项目共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.