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

EFRI CEE：一种用于理解和调节物理表观基因组的介观自下而上方法

• 批准号: 1933303
• 负责人: Andrew Feinberg
• 金额: $ 199.97万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1933303&HistoricalAwards=false
• 关键词: EFRI; CEE; mesoscopic; bottom; up

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.

该项目解决了表观遗传学如何使具有相同基因组DNA的细胞发育成不同细胞类型并以不同方式对环境线索做出反应的关键问题。主要目的是通过研究将DNA包装到染色质中的核小体的化学变化，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”来操纵细胞状态，以更好地理解和治疗人类疾病，如肥胖和癌症。该项目还将扩大代表性不足的群体在工程的参与，通过提供研究机会，在巴尔的摩的高中学生，通过Inconsistency项目，以及支持K-12教育的课程材料和活动的开发。该项目的主要目标是开发一种“自下而上”的理论，计算和实验方法，用于理解表观基因组的物理特性及其结构，组织和功能的物理机制，并研究它们对细胞可塑性和表型身份的影响。重点将是创建一个内聚模型，涉及到核小体的物理组织，在DNA和核小体水平的表观遗传修饰的互连信息，并预测更高阶的染色质组织，基因表达和细胞状态的确定。研究策略将结合信息理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。具体地说，介观染色质模型将由局部染色质变形性和全局可压缩性的物理性质定义。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，以识别驱动细胞状态转换的事件。该成果预计将首次将信息理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共同资助，和新兴前沿的研究和创新计划在新兴前沿和多学科活动的工程办公室该奖项反映了NSF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。

项目成果

Global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain.

• DOI: 10.1186/s12974-021-02228-6
• 发表时间: 2021-08-26
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Stephens KE;Zhou W;Renfro Z;Ji Z;Ji H;Guan Y;Taverna SD
• 通讯作者: Taverna SD

Dimensional Reduction for Single-Molecule Imaging of DNA and Nucleosome Condensation by Polyamines, HP1α and Ki-67.

• DOI: 10.1021/acs.jpcb.2c07011
• 发表时间: 2023-03-09
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY B
• 影响因子: 3.3
• 作者: Benning, Nils A.;Kaestel-Hansen, Jacob;Rashid, Fahad;Park, Sangwoo;Urteaga, Raquel Merino;Liao, Ting-Wei;Hao, Jingzhou;Berger, James M.;Hatzakis, Nikos S.;Ha, Taekjip
• 通讯作者: Ha, Taekjip

Genome-wide analysis of DNA-PK-bound MRN cleavage products supports a sequential model of DSB repair pathway choice

• DOI: 10.1101/2022.12.07.519501
• 发表时间: 2022-12
• 期刊: Nature Communications
• 影响因子: 16.6
• 作者: R. Deshpande;Alberto Marin-Gonzalez;T. Ha;T. Paull

Detection of haplotype-dependent allele-specific DNA methylation in WGBS data.

• DOI: 10.1038/s41467-020-19077-1
• 发表时间: 2020-10-16
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Abante J;Fang Y;Feinberg AP;Goutsias J
• 通讯作者: Goutsias J

Improving the sensitivity of in vivo CRISPR off-target detection with DISCOVER-Seq.

• DOI: 10.1038/s41592-023-01840-z
• 发表时间: 2023-05
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Zou, Roger S.;Liu, Yang;Gaido, Oscar E. Reyes;Konig, Maximilian F.;Mog, Brian J.;Shen, Leo L.;Aviles-Vazquez, Franklin;Marin-Gonzalez, Alberto;Ha, Taekjip
• 通讯作者: Ha, Taekjip