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Traditional methods that analyze bulk genomic data often obscure cell-to-cell heterogeneity, limiting the resolution of intrinsic variability within complex biological systems. To overcome this, single-cell 3D genomics has emerged, revealing chromatin architecture at the individual cell level. Advanced experimental approaches enable genome-wide chromatin contact mapping, while computational frameworks reconstruct dynamic chromatin topologies from high-dimensional data. Building on these breakthroughs, recent advances in single-cell 3D genomics have led to transformative progress in epigenetics, linking 3D genome architecture with gene regulation, cellular identity, and disease phenotypes. This review focuses on the breakthroughs in single-cell 3D genomics, demonstrating how integrated experimental, computational, and mechanistic approaches decode chromatin architecture. These insights have deepened the understanding of genome function at the single-cell level and lay the foundation for future advances in precision medicine and topology-guided therapeutic strategies.<\/jats:p>","DOI":"10.1093\/bib\/bbaf520","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T17:13:01Z","timestamp":1759770781000},"source":"Crossref","is-referenced-by-count":3,"title":["Navigating the 3D genome at single-cell resolution: techniques, computation, and mechanistic landscapes"],"prefix":"10.1093","volume":"26","author":[{"given":"Feitong","family":"Hong","sequence":"first","affiliation":[{"name":"The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China , Chengdu 610054 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaiyuan","family":"Han","sequence":"additional","affiliation":[{"name":"The Clinical Hospital 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