Chiang Michael, Brackley Chris A, Naughton Catherine, Nozawa Ryu-Suke, Battaglia Cleis, Marenduzzo Davide, Gilbert Nick
SUPA, School of Physics and Astronomy, University of Edinburgh, Peter Guthrie Tait Road, Edinburgh EH9 3FD, UK.
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK.
Cell Genom. 2024 Dec 11;4(12):100698. doi: 10.1016/j.xgen.2024.100698. Epub 2024 Nov 25.
Classical observations suggest a connection between 3D gene structure and function, but testing this hypothesis has been challenging due to technical limitations. To explore this, we developed epigenetic highly predictive heteromorphic polymer (e-HiP-HoP), a model based on genome organization principles to predict the 3D structure of human chromatin. We defined a new 3D structural unit, a "topos," which represents the regulatory landscape around gene promoters. Using GM12878 cells, we predicted the 3D structure of over 10,000 active gene topoi and stored them in the 3DGene database. Data mining revealed folding motifs and their link to Gene Ontology features. We computed a structural diversity score and identified influential nodes-chromatin sites that frequently interact with gene promoters, acting as key regulators. These nodes drive structural diversity and are tied to gene function. e-HiP-HoP provides a framework for modeling high-resolution chromatin structure and a mechanistic basis for chromatin contact networks that link 3D gene structure with function.
经典观察结果表明三维基因结构与功能之间存在联系，但由于技术限制，验证这一假设一直具有挑战性。为了探索这一点，我们开发了表观遗传高度预测性异质聚合物（e-HiP-HoP），这是一种基于基因组组织原则的模型，用于预测人类染色质的三维结构。我们定义了一种新的三维结构单元——“拓扑空间”（topos），它代表基因启动子周围的调控格局。利用GM12878细胞，我们预测了10000多个活跃基因拓扑空间的三维结构，并将它们存储在3DGene数据库中。数据挖掘揭示了折叠基序及其与基因本体特征的联系。我们计算了一个结构多样性得分，并确定了有影响力的节点——经常与基因启动子相互作用的染色质位点，它们作为关键调节因子发挥作用。这些节点驱动结构多样性并与基因功能相关联。e-HiP-HoP为高分辨率染色质结构建模提供了一个框架，以及将三维基因结构与功能联系起来的染色质接触网络的机制基础。
