Topologically associating domains (TADs) are essential components of three-dimensional (3D) genome organization and significantly influence gene transcription regulation. However, accurately identifying TADs from sparse chromatin contact maps and exploring the structural and functional elements within TADs remain challenging. To this end, we develop TADGATE, a graph attention auto-encoder that can generate imputed maps from sparse Hi-C contact maps while adaptively preserving or enhancing the underlying topological structures, thereby facilitating TAD identification. TADGATE captures specific attention patterns with two types of units within TADs and demonstrates TAD organization relates to chromatin compartmentalization with diverse biological properties. We identify many structural and functional elements within TADs, with their abundance reflecting the overall properties of these domains. We applied TADGATE to sparse and noisy Hi-C contact maps from 21 human tissues or cell lines. That improved the clarity of TAD structures, allowing us to investigate conserved and cell-type-specific boundaries and uncover cell-type-specific transcriptional regulatory mechanisms associated with topological domains. We also demonstrated TADGATE’s capability to fill in sparse single-cell Hi-C contact maps and identify TAD-like domains within them, revealing the specific domain boundaries with distinct heterogeneity and the shared backbone boundaries characterized by strong CTCF enrichment and high gene expression levels.
Publication: Nucleic Acids Research, Volume 53, Issue 4, 28 February 2025
https://doi.org/10.1093/nar/gkae1267
Author: Dachang Dang
Key Laboratory of Information Fusion Technology of Ministry of Education, School of Automation, Northwestern Polytechnical University, 1 DongXiang Road, Chang'an District, Xi’an 710072, China
Shao-Wu Zhang，Key Laboratory of Information Fusion Technology of Ministry of Education, School of Automation, Northwestern Polytechnical University, 1 DongXiang Road, Chang'an District, Xi’an 710072, China
Correspondence may also be addressed to Shao-Wu Zhang. Tel: +86 029 88431308; Fax: +86 029 88431308
Email: zhangsw@nwpu.edu.cn
Kangning Dong，NCMIS, CEMS, RCSDS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, 55 Zhongguancun East Road, Haidian District, Beijing 100190, China
School of Mathematical Sciences, University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China
Ran Duan，Department of Communications Engineering, College of Information Science, Yunnan University, East Outer Ring South Road, Chenggong District, Kunming 650500, China
Shihua Zhang，NCMIS, CEMS, RCSDS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, 55 Zhongguancun East Road, Haidian District, Beijing 100190, China
School of Mathematical Sciences, University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China
Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Xiangshan Zhinong, Xihu District, Hangzhou 310024, China
To whom correspondence should be addressed. Tel: +86 01 82541360; Fax: +86 01 82541360; Email: zsh@amss.ac.cn
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