EFRI CEE: A mesoscopic bottom-up approach for understanding and modulating the physical epigenome

该项目解决的关键问题是，表观遗传学如何使具有相同基因组DNA的细胞发育成不同的细胞类型，并以不同的方式对环境线索作出反应。主要目的是通过研究将DNA包装成染色质的核小体中的化学变化、核小体的物理致密性以及最终控制细胞行为和命运的基因的表达或沉默之间的关系，来研究表观遗传信息控制基因表达的机制。该项目整合了生物化学和生物物理实验、数学建模和计算分析，其结果有望促进“表观遗传工程”，以操纵细胞状态，从而更好地理解和治疗人类疾病，如肥胖和癌症。该项目还将通过独创性项目为巴尔的摩的高中生提供研究机会，以及开发支持K-12教育的课程材料和活动，从而扩大未被充分代表的工程群体的参与。该项目的主要目标是发展一种“自下而上”的理论、计算和实验方法，以理解表观基因组的物理特性及其结构、组织和功能背后的物理机制，并研究它们对细胞可塑性和表型身份的影响。重点将是创建一个与核小体的物理组织有关的内聚模型，在DNA和核小体水平上连接有关表观遗传修饰的信息，并预测高阶染色质组织，基因表达和细胞状态的确定。研究策略将信息论和统计力学与实验生物物理学、染色质生物化学和表观遗传生物学相结合。具体来说，介观染色质模型将由染色质局部可变形性和整体可凝聚性的物理性质来定义。通过这种“物理”透镜，该研究将把传统的染色质生物化学与大规模的染色体组织联系起来，并导致模型测试的实验，包括分子和细胞水平的成像分析，以确定驱动细胞状态转换的事件。这些结果有望首次将信息论表观遗传景观中的随机性与多能性和细胞命运的变化联系起来。该奖项由生物科学理事会分子和细胞生物科学部的遗传机制集群以及工程理事会新兴前沿和多学科活动办公室的新兴前沿研究和创新计划共同资助。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。

This project tackles the critical question of how epigenetics enable cells with the same genomic DNA to develop into different cell types and respond to environmental cues in different ways. The main objective is to investigate mechanisms whereby epigenetic information controls gene expression by studying the relationship between chemical changes in nucleosomes that package DNA into chromatin, the physical compactness of nucleosomes, and the expression or silencing of genes that ultimately control cellular behavior and fate. The project integrates biochemical and biophysical experimentation, mathematical modeling, and computational analysis, and the outcomes are expected to facilitate "epigenetic engineering" to manipulate cellular states for better understanding and treatment of of human diseases, such as obesity and cancer. The project will also broaden participation of underrepresented groups in engineering by offering research opportunities to high school students in Baltimore, through the Ingenuity project, as well as development of curricular materials and activities supporting K-12 education. The primary goal of this project is development of a "bottom-up" theoretical, computational, and experimental approach for understanding the physical properties of the epigenome and the physical mechanisms underlying its structure, organization, and function, and for studying their effects on cellular plasticity and phenotypic identity. The focus will be on creating a cohesive model that relates to the physical organization of nucleosomes, interconnects information about epigenetic modifications at the DNA and nucleosomal levels, and predicts higher order chromatin organization, gene expression, and determination of cell state. The research strategy will couple information theory and statistical mechanics with experimental biophysics, chromatin biochemistry and epigenetic biology. Specifically, the mesoscopic chromatin model will be defined by the physical properties of local chromatin deformability and global condensability. Through this "physical" lens, the research will link conventional chromatin biochemistry to large-scale chromosomal organization and lead to experiments for model testing, including imaging analysis at the molecular and cellular level to identify events that drive switching of cell states. The outcomes are expected to relate stochasticity in the information-theoretic epigenetic landscape to pluripotency and changes in cell fate for the first time.This award is co-funded by the Genetic Mechanisms cluster in the Division of Molecular and Cellular Biosciences in the Biological Sciences Directorate, and the Emerging Frontiers in Research and Innovation program in the Office of Emerging Frontiers and Multidisciplinary Activities in the Engineering Directorate.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.