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整合空间基因组学揭示了单细胞的全局结构。

Integrated spatial genomics reveals global architecture of single nuclei.

机构信息

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H.Chan School of Public Health, Boston, MA, USA.

出版信息

Nature. 2021 Feb;590(7845):344-350. doi: 10.1038/s41586-020-03126-2. Epub 2021 Jan 27.

DOI:10.1038/s41586-020-03126-2
PMID:33505024
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7878433/
Abstract

Identifying the relationships between chromosome structures, nuclear bodies, chromatin states and gene expression is an overarching goal of nuclear-organization studies. Because individual cells appear to be highly variable at all these levels, it is essential to map different modalities in the same cells. Here we report the imaging of 3,660 chromosomal loci in single mouse embryonic stem (ES) cells using DNA seqFISH+, along with 17 chromatin marks and subnuclear structures by sequential immunofluorescence and the expression profile of 70 RNAs. Many loci were invariably associated with immunofluorescence marks in single mouse ES cells. These loci form 'fixed points' in the nuclear organizations of single cells and often appear on the surfaces of nuclear bodies and zones defined by combinatorial chromatin marks. Furthermore, highly expressed genes appear to be pre-positioned to active nuclear zones, independent of bursting dynamics in single cells. Our analysis also uncovered several distinct mouse ES cell subpopulations with characteristic combinatorial chromatin states. Using clonal analysis, we show that the global levels of some chromatin marks, such as H3 trimethylation at lysine 27 (H3K27me3) and macroH2A1 (mH2A1), are heritable over at least 3-4 generations, whereas other marks fluctuate on a faster time scale. This seqFISH+-based spatial multimodal approach can be used to explore nuclear organization and cell states in diverse biological systems.

摘要

鉴定染色体结构、核体、染色质状态和基因表达之间的关系是核组织研究的首要目标。由于单个细胞在所有这些层面上似乎都具有高度的可变性，因此在同一细胞中绘制不同的模态至关重要。在这里，我们报告了使用 DNA seqFISH+在单个小鼠胚胎干细胞 (ES) 中成像 3660 个染色体位点，以及通过顺序免疫荧光和 70 个 RNA 的表达谱检测 17 个染色质标记和亚核结构。许多位点在单个小鼠 ES 细胞中始终与免疫荧光标记相关联。这些位点在单个细胞的核组织中形成“固定点”，并且经常出现在核体表面和组合染色质标记定义的区域上。此外，高表达基因似乎预先定位于活性核区，而与单个细胞中的爆发动力学无关。我们的分析还揭示了几个具有特征性组合染色质状态的不同小鼠 ES 细胞亚群。通过克隆分析，我们表明，某些染色质标记（如赖氨酸 27 上的组蛋白 H3 三甲基化 (H3K27me3) 和巨组蛋白 A1 (mH2A1)）的全局水平至少在 3-4 代内是可遗传的，而其他标记则在更快的时间尺度上波动。这种基于 seqFISH+的空间多模态方法可用于探索不同生物系统中的核组织和细胞状态。

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