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.

染色质是包装DNA的看似惰性结构，在调节基因表达中起积极作用。已经确定了具有不同组蛋白修饰和选择性蛋白质可及性的多种染色质状态。这项研究将导致这些状态之间差异的详细结构表征，以揭示染色质结构 - 功能关系并阐明基因调节的分子机制。这项研究的见解可以激发使用小分子靶向染色质调节剂并调节染色质结构以恢复正常基因表达谱的新癌症治疗策略的设计。我们研究的技术创新将引起更一般的建模社区的极大兴趣。它们可以应用于具有在各个时间尺度上发生的激活过程的其他系统。研究中使用的分子模拟技术与虚拟现实工具集结合使用，可以为令人难忘而互动的学习体验产生演示。这些示范可以激发学生对化学和分子生物学的兴趣。他们将被纳入外展计划，并在大波士顿地区介绍中学和高中生。该项目旨在使用具有隐式解决方案的近原子力场研究染色质组织。力场描述蛋白质 - 蛋白质和蛋白-DNA相互作用的精度将被系统地改善。使用先进的采样和自由能计算算法，我们将计算纤维结构形成最有问题的途径，以研究染色质折叠的动力学和机制。将原纤维结构之间的稳定性与沿折叠途径的无序构型的稳定性进行比较，可以深入了解检测原位30nm纤维的挑战。该研究还将通过表征辅助性和构型异染色质来研究关键蛋白质调节剂对染色质组织的影响。蛋白质/染色质络合物的高分辨率结构可以阐明染色质调节剂的中间核体som接触用于组蛋白标记传播。他们可以进一步揭示相位分离如何将染色质驱动到FRAP实验中揭示的凝结但动态会议中。与实验组的密切合作还将证明对于验证模型准确性和错误预测至关重要。拟议的研究将显着增强我们对在体外和原位驱动染色质折叠的分子确定剂的理解，并有助于将染色质建模转移到定量和预测方向上。该项目得到了生物科学局的分子和细胞生物科学划分的分子生物物理学和遗传机制簇的支持。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子优点和更广泛的影响审查标准来通过评估来支持的。

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