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SUMOylation modulates PRC1 clustering, but its impact on condensate properties and 3D genome architecture remains unclear. Here, we show that depletion of small ubiquitin-like modifier (SUMO) in\u00a0Drosophila wing imaginal discs transforms PRC1 condensates into large structures with reduced molecular dynamics. Biophysical modeling suggests that the changes in PRC1 self-interactions are responsible for the formation of large PRC1 condensates when SUMO is depleted. Interestingly, this biophysical reorganization occurs without global loss of the H3K27me3 mark. Instead, Hi-C reveals widespread rewiring of topologically associating domain (TAD) interactions. PRC1-bound TADs lose specific long-range contacts with each other while gaining ectopic interactions with active chromatin. These topological shifts correlate with gene misregulation independently of changes in Polycomb histone modifications. Our results establish SUMOylation as a critical regulator of PRC1 condensates, demonstrating that post-translational control of biomolecular condensation modulates 3D genome architecture and transcriptional output through mechanisms separable from histone mark deposition.<\/jats:p>","DOI":"10.1093\/nar\/gkag851","type":"journal-article","created":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T11:35:59Z","timestamp":1787484959000},"source":"Crossref","is-referenced-by-count":0,"title":["Loss of SUMOylation drives aberrant PRC1 clustering and 3D genome rewiring independent of H3K27me3"],"prefix":"10.1093","volume":"54","author":[{"given":"Nazli","family":"Akilli","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, UMR9002, Univ Montpellier, CNRS , 34396 Cedex 5,Montpellier ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul-Swann","family":"Puel","sequence":"additional","affiliation":[{"name":"Laboratoire de Biologie et Mod\u00e9lisation de la Cellule, \u00c9cole Normale Sup\u00e9rieure de Lyon, CNRS, UMR5239, Inserm U1293, Universit\u00e9 Claude Bernard Lyon 1, 69364 Cedex 07,Lyon,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6195-4754","authenticated-orcid":false,"given":"Marco Di","family":"Stefano","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, UMR9002, Univ Montpellier, CNRS , 34396 Cedex 5,Montpellier ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Muzzopappa","sequence":"additional","affiliation":[{"name":"MCD, Center for Integrative Biology (CBI), University of Toulouse, CNRS , 31400,Toulouse ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauriane","family":"Fritsch","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, UMR9002, Univ Montpellier, CNRS , 34396 Cedex 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