Chromatin is the epigenomic platform for diverse nuclear processes such as DNA repair, replication, transcription, telomere, and centromere function. In cancer cells, mutations in key processes result in DNA amplification, chromosome translocations, and chromothripsis, severely distorting the natural chromatin state. In normal and diseased states, dozens of chromatin effectors alter the physical integrity and dynamics of chromatin at the level of both single nucleosomes and arrays of nucleosomes folded into 3-dimensional shapes. Integrating these length scales, from the 10nm sized nucleosome to mitotic chromosomes, whilst jostling within the crowded environment of the cell, cannot yet be achieved by a single technology. In this review, we discuss tools that have proven powerful in the investigation of nucleosome and chromatin fiber dynamics. We also provide a deeper focus into atomic force microscopy (AFM) applications that can bridge diverse length and time scales. Using time course AFM, we observe that chromatin condensation by H1.5 is dynamic, whereas using nano-indentation force spectroscopy we observe that both histone variants and nucleosome binding partners alter material properties of individual nucleosomes. Finally, we demonstrate how high-speed AFM can visualize plasmid DNA dynamics, intermittent nucleosome-nucleosome contacts, and changes in nucleosome phasing along a contiguous chromatin fiber. Altogether, the development of innovative technologies holds the promise of revealing the secret lives of nucleosomes, potentially bridging the gaps in our understanding of how chromatin works within living cells and tissues.

染色质是多种核过程的表观基因组平台，例如 DNA 修复、复制、转录、端粒和着丝粒功能。在癌细胞中，关键过程的突变导致 DNA 扩增、染色体易位和染色体碎裂，严重扭曲了天然染色质状态。在正常和患病状态下，数十种染色质效应子在单个核小体和折叠成 3 维形状的核小体阵列水平上改变染色质的物理完整性和动力学。整合这些长度尺度，从 10 纳米大小的核小体到有丝分裂的染色体，同时在拥挤的细胞环境中相互碰撞，目前还无法通过单一技术实现。在这篇综述中，我们讨论了在核小体和染色质纤维动力学研究中被证明强大的工具。我们还更深入地关注可以弥合不同长度和时间尺度的原子力显微镜 (AFM) 应用。使用时程 AFM，我们观察到 H1.5 的染色质凝聚是动态的，而使用纳米压痕力谱我们观察到组蛋白变体和核小体结合伙伴都改变了单个核小体的材料特性。最后，我们展示了高速 AFM 如何可视化质粒 DNA 动力学、间歇性核小体-核小体接触以及沿连续染色质纤维的核小体定相变化。总而言之，创新技术的发展有望揭示核小体的秘密生命，有可能弥合我们对染色质如何在活细胞和组织中发挥作用的理解的空白。