Multiplexed imaging of nucleome architectures in single cells of mammalian tissue

The three-dimensional architecture of the genome affects genomic functions. Multiple genome architectures at different length scales, including chromatin loops, domains, compartments, and regions associated with nuclear lamina and nucleoli, have been discovered. However, how these structures are arranged in the same cell and how they are correlated with each other in different cell types in mammalian tissue are largely unknown. Here, we developed Multiplexed Imaging of Nucleome Architectures that measures multiscale chromatin folding, copy numbers of numerous RNA species, and associations of numerous genomic regions with nuclear lamina, nucleoli and surface of chromosomes in the same, single cells. We applied this method in mouse fetal liver, and identified de novo cell-type-specific chromatin architectures associated with gene expression, as well as chromatin organization principles independent of cell type. Polymer simulation showed that both intra-chromosomal self-associating interactions and extra-chromosomal interactions are necessary to establish the observed organization. Our experiments and modeling provide a multiscale and multi-faceted picture of chromatin folding and nucleome architectures in mammalian tissue and illustrate physical principles for maintaining chromatin organization. Here we submit our bulk RNA-sequencing data on E14.5 mouse fetal liver, used in the study to validate image-based RNA profiling results. Bulk mRNA sequencing from mouse embryonic day 14.5 fetal liver tissue基因组的三维架构对基因组功能具有调控作用。目前已发现多种不同长度尺度的基因组架构，包括染色质环、染色质结构域、区室，以及与核纤层和核仁相关的基因组区域。然而，这些结构在同一细胞内的排布模式，以及它们在哺乳动物组织不同细胞类型间的相互关联机制，在很大程度上仍未明确。本研究开发了核体架构多重成像（Multiplexed Imaging of Nucleome Architectures）技术，可在单个细胞内同步检测多尺度染色质折叠状态、多种RNA物种的拷贝数，以及大量基因组区域与核纤层、核仁及染色体表面的关联情况。我们将该技术应用于小鼠胎肝组织，全新鉴定出与基因表达相关的细胞类型特异性染色质架构，以及不依赖细胞类型的染色质组织通用原则。聚合物模拟实验证实，染色质内部的自相互作用与染色体外的相互作用均为构建观测到的染色质架构所必需。本研究的实验与建模工作为哺乳动物组织内的染色质折叠与核体架构提供了多尺度、多维度的全景图景，并阐明了维持染色质组织的物理原理。本文同步提交本研究中用于验证基于成像的RNA分析结果的E14.5小鼠胎肝批量RNA测序（bulk RNA-sequencing）数据，即来自小鼠胚胎第14.5天胎肝组织的批量mRNA测序数据。