Mechanobiology Institute and Department of Biological Sciences, NUS, Singapore.
Biophys J. 2013 Feb 5;104(3):553-64. doi: 10.1016/j.bpj.2012.12.033.
Stem cells integrate signals from the microenvironment to generate lineage-specific gene expression programs upon differentiation. Undifferentiated cell nuclei are easily deformable, with an active transcriptome, whereas differentiated cells have stiffer nuclei and condensed chromatin. Chromatin organization in the stem cell state is known to be highly dynamic but quantitative characterizations of its plasticity are lacking. Using fluorescence imaging, we study the spatio-temporal dynamics of nuclear architecture and chromatin compaction in mouse embryonic stem (ES) cells and differentiated states. Individual ES cells exhibit a relatively narrow variation in chromatin compaction, whereas primary mouse embryonic fibroblasts (PMEF) show broad distributions. However, spatial correlations in chromatin compaction exhibit an emergent length scale in PMEFs, although they are unstructured and longer ranged in ES cells. We provide evidence for correlated fluctuations with large amplitude and long intrinsic timescales, including an oscillatory component, in both chromatin compaction and nuclear area in ES cells. Such fluctuations are largely frozen in PMEF. The role of actin and Lamin A/C in modulating these fluctuations is described. A simple theoretical formulation reproduces the observed dynamics. Our results suggest that, in addition to nuclear plasticity, correlated spatio-temporal structural fluctuations of chromatin in undifferentiated cells characterize the stem cell state.
干细胞整合来自微环境的信号，在分化时产生谱系特异性基因表达程序。未分化的细胞核容易变形，具有活跃的转录组，而分化的细胞具有更硬的核和浓缩的染色质。干细胞状态下的染色质组织已知具有高度的动态性，但缺乏对其可塑性的定量描述。我们使用荧光成像研究了小鼠胚胎干细胞（ES 细胞）和分化状态下核结构和染色质紧缩的时空动力学。单个 ES 细胞显示出相对较窄的染色质紧缩变化范围，而原代小鼠胚胎成纤维细胞（PMEF）则显示出较宽的分布。然而，PMEF 中染色质紧缩的空间相关性表现出一种突发的长度尺度，尽管它们在 ES 细胞中是无结构的和更长的范围。我们提供了证据表明，在 ES 细胞中，染色质紧缩和核面积都存在具有大振幅和长固有时间尺度的相关波动，包括一个振荡成分。这些波动在 PMEF 中很大程度上被冻结。描述了肌动蛋白和核纤层蛋白 A/C 在调节这些波动中的作用。一个简单的理论公式再现了观察到的动力学。我们的结果表明，除了核可塑性外，未分化细胞中染色质的相关时空结构波动特征化了干细胞状态。
