单分子操控与单分子显微成像是现代生物物理学(biological physics)中的创新技术。本项目中我们将两种技术集成在一起，并应用到核小体和染色质的组装及动力学研究中。正确的染色质结构是保证DNA复制、转录、重组和修复等正常进行的基础。染色质结构变化及调控的分子机理是理解细胞增殖发育和分化过程中重要基因的表达差异及其表观遗传学的关键。我们用单分子磁镊研究短DNA链上单个核小体的原位组装，同时用单分子光谱监测与该DNA链相互作用的蛋白质的数量与时序,以及核小体在染色质重塑因子等作用下的移位等。其次我们用单分子力谱研究预先组装好的染色质结构转变，用单分子光谱研究伴随这些结构转变的蛋白质的动力学。我们还将定量比较各种表观遗传机制（如DNA化学修饰以及组蛋白变体等）对单个核小体和染色质纤维结构和动力学的调控，为阐明各种表观遗传机制的作用机理提供物理学基础。

Single molecule manipulation and single molecule imaging are two cutting-edge techniques for modern biological physics. In this project we will make a combination of them to study the longstanding fundamental problems of nucleosome assembly and chromatin dynamics. In eukaryotic cell chromatin is hierarchically compacted with different folding levels and organized in three dimensions via interacting with other nuclear structures within the nucleus. Nucleosomes form the fundamental repeating units of eukaryotic chromatin and are thought to carry epigenetically inherited information in the form of covalent modifications of their core histones. We will first perform in situ studies on the assembly of individual nucleosomes on short DNA molecules by using magnetic tweezers which are integrated onto a fluorescence microscope. At the same time we will use single molecule spectroscopy to monitor interactions of histones with tethered DNA, and nucleosome sliding caused by chromatin remodeling complexes as well. Secondly, we will study the structural changes of pre-assembled chromatins under manipulation of magnetic tweezers. Again, single molecule spectroscopy can be used to monitor the behaviors of different nucleosome proteins accompanying the structural changes of the chromatin. In all these studies, we will investigate how the DNA methylation, histone modifications and variants and chromatin remodeling complexes are involved in regulating higher order chromatin dynamics. The results of our studies will provide important mechanistic insights into the biological function of chromatin structure and organization in epigenetic inheritance, development and cell differentiation, and epigenetic de-regulation in human diseases.