Monitoring the three-dimensional motion of chromatin at single molecule resolution

项目总结 间期核中染色体位置不是静止的，而是移动的，这一概念并不是 新的。然而，染色质运动的机械性作用通常被低估。事实上，纳米尺度 染色质的运动可能调节DNA与包括染色质在内的调节分子的相互作用 效应器、转录因子和非编码RNA，从而影响基因表达的全球模式。 不幸的是，支持染色质运动在这些活动中起重要作用的实验证据是 稀疏。因此，目前还不清楚染色质动力学的变化是促进了这些生物过程，还是仅仅是 后果。 这个项目的目标是量化整个哺乳动物细胞核中的染色质运动，并探索 它在基因组功能中的机械作用。为此，拟议的研究结合了多学科 关注染色质运动与表观遗传调控、DNA损伤和 转录，最终目的是理解从表观遗传修饰到表型基因的因果关系 表情。建议的项目如下： 项目1以纳米分辨率绘制3D染色质运动图。我们将大量整合这些数据 将科学方法引入我们的创新成像系统，以优化染色质测量工具箱。这个 工具箱将包括数据驱动的3D成像系统和数据科学支持的图像信息学软件。 项目2研究染色质运动与表观遗传修饰和转录之间的联系。 我们将探索染色质运动和表观遗传修饰之间的相互作用以及 分别转录。因此，这些实验研究可以提供适当的数学模型。 使染色质重塑和基因表达中的反应网络正式化。 这些项目产生的结果具有揭示染色质之间基本联系的巨大潜力 运动和基因表达，这将改变我们对疾病机制的理解，并促进 治疗性干预的发展。

PROJECT SUMMARY The notion that the positions of chromosomal loci within the interphase nucleus are not static, but move, is not new. However, the mechanistic role of the chromatin motion is usually underestimated. In fact, the nanoscale motion of chromatin may modulate the interaction of DNA with regulatory molecules, including chromatin effectors, transcription factors and non-coding RNAs, thus impacting the global patterns of gene expression. Unfortunately, experimental evidence supporting an essential role of chromatin motion in these activities is sparse. Thus, it is unclear if changes in chromatin dynamics facilitate these biological processes or are simply consequences. The goal of this project is to quantify the chromatin motion throughout the mammalian nucleus and to explore its mechanistic role in genome functions. To this end, the proposed research combines multidisciplinary approaches to concentrate on the link of chromatin motion with epigenetic regulation, DNA damage, and transcription, with the ultimate goal to understand the causality from epigenetic modification to phenotypic gene expression. The proposed projects are listed as below, Project 1 Map the chromatin motion in 3D with nanometer resolution. We will heavily incorporate the data science approach into our innovative imaging system to optimize the toolbox of measuring the chromatin. The toolbox will include the data-driven 3D imaging system and data science supported image informatics software. Project 2 Investigate the link between chromatin motion and epigenetic modification and transcription. We will explore the reciprocal interactions between chromatin motion and epigenetic modifications as well as transcription, respectively. These experimental investigations can feed proper mathematical models, therefore to formalize the reaction network in chromatin remodeling and gene expression. Results generated from these projects have great potential to reveal fundamental links between chromatin motion and gene expression, which will transform our understanding of disease mechanism and facilitate the development of therapeutic intervention.