Li Chong, Bonder Marc Jan, Syed Sabriya, Jensen Matthew, Gerstein Mark B, Zody Michael C, Chaisson Mark J P, Talkowski Michael E, Marschall Tobias, Korbel Jan O, Eichler Evan E, Lee Charles, Shi Xinghua
Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, Pennsylvania 19122, USA.
Genome Res. 2024 Dec 23;34(12):2304-2318. doi: 10.1101/gr.279419.124.
The human genome is packaged within a three-dimensional (3D) nucleus and organized into structural units known as compartments, topologically associating domains (TADs), and loops. TAD boundaries, separating adjacent TADs, have been found to be well conserved across mammalian species and more evolutionarily constrained than TADs themselves. Recent studies show that structural variants (SVs) can modify 3D genomes through the disruption of TADs, which play an essential role in insulating genes from outside regulatory elements' aberrant regulation. However, how SV affects the 3D genome structure and their association among different aspects of gene regulation and candidate -regulatory elements (cCREs) have rarely been studied systematically. Here, we assess the impact of SVs intersecting with TAD boundaries by developing an integrative Hi-C analysis pipeline, which enables the generation of an in-depth catalog of TADs and TAD boundaries in human lymphoblastoid cell lines (LCLs) to fill the gap of limited resources. Our catalog contains 18,865 TADs, including 4596 sub-TADs, with 185 SVs (TAD-SVs) that alter chromatin architecture. By leveraging the ENCODE registry of cCREs in humans, we determine that 34 of 185 TAD-SVs intersect with cCREs and observe significant enrichment of TAD-SVs within cCREs. This study provides a database of TADs and TAD-SVs in the human genome that will facilitate future investigations of the impact of SVs on chromatin structure and gene regulation in health and disease.
人类基因组被包装在三维（3D）细胞核内，并组织成称为区室、拓扑相关结构域（TAD）和环的结构单元。已发现分隔相邻TAD的TAD边界在哺乳动物物种中高度保守，并且比TAD本身在进化上受到更多限制。最近的研究表明，结构变异（SV）可通过破坏TAD来修饰3D基因组，而TAD在使基因免受外部调控元件异常调控方面起着至关重要的作用。然而，SV如何影响3D基因组结构以及它们在基因调控和候选调控元件（cCRE）不同方面之间的关联，很少得到系统研究。在此，我们通过开发一种综合的Hi-C分析流程来评估与TAD边界相交的SV的影响，该流程能够生成人类淋巴母细胞系（LCL）中TAD和TAD边界的深入目录，以填补资源有限的空白。我们的目录包含18,865个TAD，包括4596个亚TAD，其中有185个改变染色质结构的SV（TAD-SV）。通过利用人类cCRE的ENCODE登记库，我们确定185个TAD-SV中有34个与cCRE相交，并观察到cCRE内TAD-SV的显著富集。这项研究提供了一个人类基因组中TAD和TAD-SV的数据库，将有助于未来对SV在健康和疾病中对染色质结构和基因调控影响的研究。
