A comprehensive benchmarking with interpretation and operational guidance for the hierarchy of topologically associating domains

Jingxuan Xu, Xiang Xu, Dandan Huang, Yawen Luo, Lin Lin, Xuemei Bai, Yang Zheng, Qian Yang, Yu Cheng, An Huang, Jingyi Shi, Xiaochen Bo (), Jin Gu () and Hebing Chen ()
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Jingxuan Xu: Peking University Cancer Hospital & Institute
Xiang Xu: Academy of Military Medical Science
Dandan Huang: Peking University Shougang Hospital
Yawen Luo: Academy of Military Medical Science
Lin Lin: Academy of Military Medical Science
Xuemei Bai: Academy of Military Medical Science
Yang Zheng: Academy of Military Medical Science
Qian Yang: Academy of Military Medical Science
Yu Cheng: Peking University Cancer Hospital & Institute
An Huang: Peking University Cancer Hospital & Institute
Jingyi Shi: Peking University Cancer Hospital & Institute
Xiaochen Bo: Academy of Military Medical Science
Jin Gu: Peking University Cancer Hospital & Institute
Hebing Chen: Academy of Military Medical Science

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48593-7

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