Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Academy of Military Medical Science, Beijing, 100850, China.
Nat Commun. 2024 May 23;15(1):4376. doi: 10.1038/s41467-024-48593-7.
Topologically associating domains (TADs), megabase-scale features of chromatin spatial architecture, are organized in a domain-within-domain TAD hierarchy. Within TADs, the inner and smaller subTADs not only manifest cell-to-cell variability, but also precisely regulate transcription and differentiation. Although over 20 TAD callers are able to detect TAD, their usability in biomedicine is confined by a disagreement of outputs and a limit in understanding TAD hierarchy. We compare 13 computational tools across various conditions and develop a metric to evaluate the similarity of TAD hierarchy. Although outputs of TAD hierarchy at each level vary among callers, data resolutions, sequencing depths, and matrices normalization, they are more consistent when they have a higher similarity of larger TADs. We present comprehensive benchmarking of TAD hierarchy callers and operational guidance to researchers of life science researchers. Moreover, by simulating the mixing of different types of cells, we confirm that TAD hierarchy is generated not simply from stacking Hi-C heatmaps of heterogeneous cells. Finally, we propose an air conditioner model to decipher the role of TAD hierarchy in transcription.
拓扑关联域（TAD）是染色质空间结构的兆碱基规模特征，它们在域内 TAD 层次结构中组织。在 TAD 内，内部和较小的亚 TAD 不仅表现出细胞间的可变性，而且还能精确地调节转录和分化。尽管有超过 20 个 TAD 调用者能够检测 TAD，但由于输出不一致和对 TAD 层次结构的理解有限，它们在生物医学中的可用性受到限制。我们在各种条件下比较了 13 种计算工具，并开发了一种评估 TAD 层次结构相似性的度量标准。尽管在每个级别上 TAD 层次结构的输出在调用者、数据分辨率、测序深度和矩阵归一化之间存在差异，但当它们具有更大 TAD 的更高相似性时，它们更一致。我们对 TAD 层次结构调用者进行了全面的基准测试，并为生命科学研究人员提供了操作指导。此外，通过模拟不同类型细胞的混合，我们证实 TAD 层次结构不是简单地从异质细胞的 Hi-C 热图堆叠中产生的。最后，我们提出了一个空调模型来破译 TAD 层次结构在转录中的作用。
