Evaluating the role of the nuclear microenvironment in gene function by population-based modeling.
Evaluating the role of the nuclear microenvironment in gene function by population-based modeling.
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DOI：
10.1038/s41594-023-01036-1
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发表时间：
2023-08
影响因子：
16.8
通讯作者：
Alber, Frank
中科院分区：
文献类型：
--
作者：
Yildirim, Asli;Hua, Nan;Boninsegna, Lorenzo;Zhan, Yuxiang;Polles, Guido;Gong, Ke;Hao, Shengli;Li, Wenyuan;Zhou, Xianghong Jasmine;Alber, Frank
染色体相对于核体的核折叠是基因功能的组成部分。在这里，我们证明了基于群体的建模-从合奏Hi-C数据-提供了一个详细的描述基因的核微环境及其在基因功能中的作用。我们通过基因组区域相对于核体的亚核位置、局部染色质致密化和染色质区室化的偏好来定义微环境。在单细胞模型中确定这些结构描述符，从而揭示细胞之间的结构变异性。我们证明了基因组区域的微环境与其在基因转录、复制和染色质区室化中的功能潜力有关。一些染色质区域具有对单一微环境的强烈偏好，这是由于与大多数细胞中的特定核小体相关。其他染色质显示出高度的结构变异性，这是功能异质性的一个强有力的指标。此外，我们确定了专门的核微环境，区分不同功能状态的染色质，并揭示了核斑点在染色体组织中的关键作用。我们证明，我们的方法产生高度预测性的三维基因组结构，准确地再现数据从各种正交实验，从而大大扩展了Hi-C数据分析的范围。在这里，使用基于群体的建模对合奏Hi-C数据，作者提供了一个广泛的概述基因染色质微环境如何影响其潜在的参与不同的功能，如转录，DNA复制和染色质区室化。他们的结果揭示了核斑点在基因组组织中的关键作用。
The nuclear folding of chromosomes relative to nuclear bodies is an integral part of gene function. Here, we demonstrate that population-based modeling—from ensemble Hi-C data—provides a detailed description of the nuclear microenvironment of genes and its role in gene function. We define the microenvironment by the subnuclear positions of genomic regions with respect to nuclear bodies, local chromatin compaction, and preferences in chromatin compartmentalization. These structural descriptors are determined in single-cell models, thereby revealing the structural variability between cells. We demonstrate that the microenvironment of a genomic region is linked to its functional potential in gene transcription, replication, and chromatin compartmentalization. Some chromatin regions feature a strong preference for a single microenvironment, due to association with specific nuclear bodies in most cells. Other chromatin shows high structural variability, which is a strong indicator of functional heterogeneity. Moreover, we identify specialized nuclear microenvironments, which distinguish chromatin in different functional states and reveal a key role of nuclear speckles in chromosome organization. We demonstrate that our method produces highly predictive three-dimensional genome structures, which accurately reproduce data from a variety of orthogonal experiments, thus considerably expanding the range of Hi-C data analysis. Here, using population-based modeling on ensemble Hi-C data, the authors provide an expansive overview of how the genic chromatin microenvironment influences its potential involvement in different functions, such as transcription, DNA replication, and chromatin compartmentalization. Their results unveil a key role of nuclear speckles in genome organization.
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