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Dynamic alterations of three\u2010dimensional (3D) genomic spatial structure, driven by chromatin reorganization, play a critical role in cell fate determination, but their relevance in therapy\u2010induced senescence (TIS) remains underexplored. Here, we perform an integrative multi\u2010omics analysis of Hi\u2010C, ATAC\u2010seq, CUT&amp;RUN, and RNA\u2010seq in primary human fibroblasts undergoing TIS induced by ionizing radiation (RAD) or bleomycin (BLEO). We show that TIS leads to global chromatin decompaction, weakened compartmentalization, and destabilization of topologically associated domains (TADs), alongside widespread loss and rewiring of chromatin loops. Notably, RAD and BLEO elicit distinct changes in distance\u2010dependent compartment strength and enhancer\u2013promoter (E\u2010P) loop patterns, reflecting divergent 3D regulatory programs. Importantly, TIS reshapes the chromatin environment around senescence\u2010associated secretory phenotype (SASP) genes, while their adjacent regions exhibit reduced chromatin interactions, allowing transcriptional activation. Our study reveals that 3D genome remodeling in TIS is highly plastic and context\u2010dependent and discloses spatial regulation of gene expression during therapy\u2010induced cellular senescence.<\/jats:p>","DOI":"10.1111\/acel.70366","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T12:13:09Z","timestamp":1767701589000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Spatial Reorganization of Chromatin Architecture Shapes the Expression Phenotype of Therapy\u2010Induced Senescent Cells"],"prefix":"10.1111","volume":"25","author":[{"given":"Ge","family":"Zhang","sequence":"first","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, Chinese 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