CAREER: Chromatin Folding from the Bottom-up

职业：染色质自下而上折叠

• 批准号: 2042362
• 负责人: Bin Zhang
• 金额: $ 110万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2042362&HistoricalAwards=false
• 关键词: CAREER; Chromatin; Folding; Bottom; up

Chromatin, the seemingly inert structure that packages the DNA, plays an active role in regulating gene expression. Multiple chromatin states with distinct patterns of histone modifications and selective protein accessibility have been identified. This research will lead to a detailed structural characterization of the differences between these states to reveal the chromatin structure-function relationship and elucidate the molecular mechanisms of gene regulation. Insights from this study could inspire the design of new cancer therapeutic strategies using small molecules to target chromatin regulators and modulate chromatin structure to restore normal gene expression profiles. Technological innovations from our study will be of great interest to the more general modeling community. They can be applied to other systems with activated processes that occur over a wide range of timescales. Molecular simulation techniques used in the research, when combined with virtual reality toolsets, could produce demonstrations for a memorable and interactive learning experience. These demonstrations could inspire students’ interest in chemistry and molecular biology. They will be incorporated into an outreach program and presented to middle school and high school students in the Greater Boston area. The project aims to study the chromatin organization using a near-atomistic force field with implicit solvation. The force field's accuracy in describing protein-protein and protein-DNA interactions will be systematically improved. Using advanced sampling and free energy computation algorithms, we will compute the most probable pathways for fibril structure formation to study the dynamics and mechanism of chromatin folding. Comparing the stability between fibril structures with that of disordered configurations along the folding pathway may provide insight into the challenge of detecting the 30nm fiber in situ. The research will also investigate the impact of key protein regulators on chromatin organization by characterizing both facultative and constitutive heterochromatin. High-resolution structures for protein/chromatin complexes can elucidate how chromatin regulators mediate long-range nucleosomal contacts for histone mark propagation. They can further reveal how phase separation drives chromatin into condensed but dynamic conformations revealed in FRAP experiments. Close collaboration with experimental groups will also prove crucial for validating model accuracy and falsifying predictions. The proposed research will significantly enhance our understanding of the molecular determinants that drive chromatin folding in vitro and situ and help move chromatin modeling towards quantitative and predictive directions. This project is supported by the Molecular Biophysics and Genetic Mechanisms Clusters of the Molecular and Cellular Biosciences Division in the 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.

染色质，包裹DNA的看似惰性的结构，在调节基因表达中起着积极的作用。具有组蛋白修饰和选择性蛋白可及性的多种染色质状态已被确定。本研究将对这些状态之间的差异进行详细的结构表征，揭示染色质结构-功能关系，阐明基因调控的分子机制。这项研究的见解可以启发设计新的癌症治疗策略，利用小分子靶向染色质调节剂和调节染色质结构来恢复正常的基因表达谱。我们研究中的技术创新将引起更广泛的建模社区的极大兴趣。它们可以应用于其他具有激活过程的系统，这些过程发生在广泛的时间尺度范围内。研究中使用的分子模拟技术，当与虚拟现实工具集相结合时，可以为难忘的交互式学习体验提供演示。这些演示可以激发学生对化学和分子生物学的兴趣。它们将被纳入一个拓展项目，并呈现给大波士顿地区的初中生和高中生。该项目旨在利用具有隐式溶剂化的近原子力场研究染色质组织。力场在描述蛋白质-蛋白质和蛋白质- dna相互作用方面的准确性将得到系统的提高。利用先进的采样和自由能计算算法，我们将计算出纤维结构形成的最可能途径，以研究染色质折叠的动力学和机制。通过比较纤维结构与无序结构在折叠路径上的稳定性，可以深入了解原位检测30nm纤维的挑战。该研究还将通过表征兼性和组成性异染色质来研究关键蛋白质调节因子对染色质组织的影响。蛋白质/染色质复合物的高分辨率结构可以阐明染色质调节剂如何介导组蛋白标记增殖的远程核小体接触。它们可以进一步揭示相分离如何驱动染色质进入FRAP实验中揭示的浓缩但动态的构象。与实验小组的密切合作对于验证模型准确性和伪造预测也至关重要。所提出的研究将大大提高我们对驱动染色质在体外和原位折叠的分子决定因素的理解，并有助于将染色质建模推向定量和预测方向。该项目得到了生物科学理事会分子和细胞生物科学部分子生物物理学和遗传机制组的支持。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。

项目成果

Molecular determinants for the layering and coarsening of biological condensates: Special Issue: Emerging Investigators

生物凝聚物分层和粗化的分子决定因素：特刊：新兴研究者

• DOI: 10.1002/agt2.306
• 发表时间: 2022
• 期刊: Aggregate
• 影响因子: 18.8
• 作者: Latham, Andrew P.;Zhang, Bin
• 通讯作者: Zhang, Bin