Investigating human chromosome organization by whole-genome simulations
Investigating human chromosome organization by whole-genome simulations
复制标题
通过全基因组模拟研究人类染色体组织
DOI：
10.1016/j.bpj.2022.11.1728
复制
发表时间：
2023
影响因子：
3.4
通讯作者：
Onuchic, José N.
中科院分区：
文献类型：
--
作者：
Mello, Matheus F.;Dodero-Rojas, Esteban;Oliveira Jr, Antonio B.;Contessoto, Vinicius;Onuchic, José N.
染色体组构及其与基因表达和调控的关系一直是理论家和实验家们研究的重点。设计了许多实验程序，如Hi-C或ChIA-PET，以捕获染色体的结构信息。提出了几种理论模型来理解染色体区室化的基本原理。MiChroM是一个描述间期染色体区室化行为的模型。与实验数据相比，计算机接触图的一致性表明A/B区室的相分离是决定单个染色体结构的关键特征。在这项工作中，我们使用Open-MiChroM软件以50 kb的分辨率模拟了GM 12878人类细胞的46条染色体，试图了解整个基因组的核组织是否依赖于单个染色体组织所观察到的相同原则。我们的模拟所产生的结构的合奏捕捉领土内的染色体组织和相分离的染色质隔间。在染色体区域内，活性染色质优先定位于外周，而非活性染色质位于内部。每个区域的染色体内接触图和形状度量与实验数据一致。由此产生的基因组结构类似于倒置的细胞核构型，活性染色质朝向外周。在染色体之间的界面中，我们还观察到隔室的相分离。然而，与实验数据相比，染色体间图谱呈现出更高的异染色质位点接触概率。这些结果表明，染色质与其他核特征（如纤层）的相互作用极大地影响了染色体间的相互作用，同时也影响了染色体在核中的整体定位。
Both theoreticians and experimentalists have been dedicating significant effort to studying chromosome organization and its relation to gene expression and regulation. Many experimental procedures were designed, such as Hi-C or ChIA-PET, to capture structural information of chromosomes. Several theoretical models were proposed to understand the principles underlying chromosome compartmentalization. MiChroM is a model that describes the compartmentalization behavior of interphase chromosomes. Compared to experimental data, the agreement of the in silico contact maps suggested that phase separation of A/B compartments is a key feature determining the structure of individual chromosomes. In this work, we use the Open-MiChroM software to simulate the 46 chromosomes of a GM12878 human cell at 50 kb resolution, seeking to understand whether the nuclear organization of the whole genome would rely on the same principles observed for the organization of a single chromosome. The ensemble of structures generated by our simulations captures chromosome organization within territories and phase separation of chromatin compartments. Inside a chromosome territory, active chromatin localizes preferentially in the periphery, while inactive chromatin lies on the inside. The intra-chromosomal contact maps and the shape metrics of each territory are consistent with experimental data. The resulting genome architecture resembles the inverted nucleus configuration, with active chromatin towards the periphery. In the interface between chromosomes, we also observe phase separation of compartments. However, the inter-chromosomal maps present higher contact probabilities for heterochromatin loci when compared to the experimental data. These results suggest that the interactions of chromatin with other nuclear features like the lamina greatly influences inter-chromosomal interactions while also affecting the overall positioning of chromosomes in the nucleus.