Shenzhen Research Institute of Big Data, Chinese University of Hong Kong-Shenzhen, Shenzhen 518172, Guangdong, China.
Department of Computational Medicine and Bioinformatics.
Mol Biol Cell. 2021 Aug 19;32(18):1624-1633. doi: 10.1091/mbc.E20-08-0502. Epub 2021 Apr 28.
Histone deacetylase inhibitors, such as valproic acid (VPA), have important clinical therapeutic and cellular reprogramming applications. They induce chromatin reorganization that is associated with altered cellular morphology. However, there is a lack of comprehensive characterization of VPA-induced changes of nuclear size and shape. Here, we quantify 3D nuclear morphology of primary human astrocyte cells treated with VPA over time (hence, 4D). We compared volumetric and surface-based representations and identified seven features that jointly discriminate between normal and treated cells with 85% accuracy on day 7. From day 3, treated nuclei were more elongated and flattened and then continued to morphologically diverge from controls over time, becoming larger and more irregular. On day 7, most of the size and shape descriptors demonstrated significant differences between treated and untreated cells, including a 24% increase in volume and 6% reduction in extent (shape regularity) for treated nuclei. Overall, we show that 4D morphometry can capture how chromatin reorganization modulates the size and shape of the nucleus over time. These nuclear structural alterations may serve as a biomarker for histone (de-)acetylation events and provide insights into mechanisms of astrocytes-to-neurons reprogramming.
组蛋白去乙酰化酶抑制剂，如丙戊酸（VPA），具有重要的临床治疗和细胞重编程应用。它们诱导染色质重排，与细胞形态改变相关。然而，VPA 诱导的核大小和形状变化缺乏全面的特征描述。在这里，我们对用 VPA 处理的原代人星形胶质细胞进行了 3D 核形态的定量分析（因此，是 4D）。我们比较了体积和基于表面的表示，并确定了七个特征，这些特征在第 7 天能够以 85%的准确率将正常细胞和处理细胞区分开来。从第 3 天开始，处理过的核变得更加细长和平坦，然后随着时间的推移继续与对照细胞在形态上发生分歧，变得更大更不规则。在第 7 天，大多数大小和形状描述符在处理和未处理的细胞之间表现出显著差异，包括处理核的体积增加 24%，形状规则性降低 6%。总的来说，我们表明 4D 形态计量学可以捕捉到染色质重排如何随时间调节核的大小和形状。这些核结构的改变可以作为组蛋白（去）乙酰化事件的生物标志物，并为星形胶质细胞向神经元重编程的机制提供见解。
