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Recent work implicates genome geometry in encoding transcriptional memory, with nanoscopic chromatin packing domains (PDs) serving as structural units that stabilize or reprogram transcriptional states. One powerful, yet underexplored regulator of this architecture is the nuclear ionic environment. Divalent cations can stabilize PDs through charge screening and phosphate bridging, suggesting a direct physicochemical mechanism linking ions to genome organization. In this study, we show that manipulating nuclear divalent cations is sufficient to reshape chromatin architecture, transcriptional output, and cellular resilience in living human cancer cells. Selective cation depletion (BAPTA\u2010AM, APDAP\u2010AM) produces smaller, less compact PDs and diminishes H3K9me3\u2010enriched heterochromatic cores, structural anchors of transcriptional memory. In contrast, magnesium enrichment enhances packing density and domain maturation.\u00a0Live\u2010cell\u00a0nanoscopy\u00a0reveals that chromatin packing scaling responds within minutes to ionic perturbation. Transcriptomic profiling\u00a0demonstrates\u00a0coordinated gene expression changes and\u00a0reduced adaptive plasticity, while chelator pretreatment increases chemotherapy sensitivity. Together, these findings\u00a0identify\u00a0nuclear ions as rapid, reversible regulators of chromatin packing domains and transcriptional memory, revealing ionic homeostasis as a fundamental mechanism linking genome architecture to cellular adaptation.<\/jats:p>","DOI":"10.1002\/advs.76786","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T08:38:59Z","timestamp":1786610339000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chromatin Packing Domain Engineering Through the Manipulation of Nuclear Cationic States"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0909-9647","authenticated-orcid":false,"given":"Cody L.","family":"Dunton","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrillo","family":"Paola Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"},{"name":"Chemistry of Life Processes Institute Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luay","family":"Almassalha","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Northwestern Memorial Hospital  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing Shun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyi","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Acosta","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I Chae","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Frederick","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Hogg","sequence":"additional","affiliation":[{"name":"Department of Chemistry Durham University  Durham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saira","family":"John","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4688-3000","authenticated-orcid":false,"given":"J. 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Gareth","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Chemistry Durham University  Durham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikkert J.","family":"Nap","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"},{"name":"Chemistry of Life Processes Institute Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igal","family":"Szleifer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"},{"name":"Chemistry of Life Processes Institute Northwestern University  Evanston Illinois USA"},{"name":"Department of Chemistry Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Backman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Center for Physical Genomics and Engineering Northwestern University  Evanston Illinois USA"},{"name":"Chemistry of Life Processes Institute Northwestern University  Evanston Illinois USA"},{"name":"Robert H. 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