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In the majority of cases, FSHD is associated with the contraction of the D4Z4 macrosatellite repeat array at the 4q35 locus, leading to the inappropriate activation of\n                    <jats:italic>DUX4<\/jats:italic>\n                    , normally expressed during early embryogenesis. In FSHD, the genetic contraction is accompanied by hypomethylation of the D4Z4 array. Although a connection between DNA hypomethylation and\n                    <jats:italic>DUX4<\/jats:italic>\n                    expression has been suggested, the precise mechanisms that regulate\n                    <jats:italic>DUX4<\/jats:italic>\n                    transcription remain incompletely defined. The post-translational modification by SUMO was shown previously to repress the expression of\n                    <jats:italic>Dux<\/jats:italic>\n                    , the\n                    <jats:italic>DUX4<\/jats:italic>\n                    homolog, in mouse embryonic stem cells. Based on these findings, we explored here the contribution of SUMOylation in the regulation of\n                    <jats:italic>DUX4<\/jats:italic>\n                    in human muscle cells. We demonstrate that TAK\u2011981 (subasumstat), a selective SUMOylation inhibitor, promotes transcriptional reprogramming of the 4q35 locus and induces\n                    <jats:italic>DUX4<\/jats:italic>\n                    expression. Importantly, this activation occurs independently of changes in DNA methylation or SMCHD1 ATPase activity. Our findings identify SUMOylation inhibition as a novel regulatory process driving\n                    <jats:italic>DUX4<\/jats:italic>\n                    expression. This work uncovers the importance of SUMOylation in the epigenetic control of the 4q35 locus and\n                    <jats:italic>DUX4<\/jats:italic>\n                    transcription, providing a potential therapeutic strategy to modulate\n                    <jats:italic>DUX4<\/jats:italic>\n                    expression in FSHD.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-33624-0","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T09:54:52Z","timestamp":1767952492000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chemical inhibition of SUMOylation activates the FSHD locus"],"prefix":"10.1038","volume":"16","author":[{"given":"Alice","family":"Nordlinger","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lo\u00e9va","family":"Morin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Andrieux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean Philippe","family":"Trani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"Perrin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Eudes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Bigot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Dejean","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fr\u00e9d\u00e9rique","family":"Magdinier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"33624_CR1","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1038\/s41580-022-00500-y","volume":"23","author":"ACO Vertegaal","year":"2022","unstructured":"Vertegaal, A. C. O. Signalling mechanisms and cellular functions of SUMO. Nat Rev Mol Cell Biol 23, 715\u2013731. https:\/\/doi.org\/10.1038\/s41580-022-00500-y (2022).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"33624_CR2","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nrc.2016.143","volume":"17","author":"JS Seeler","year":"2017","unstructured":"Seeler, J. S. & Dejean, A. SUMO and the robustness of cancer. Nat Rev Cancer 17, 184\u2013197. https:\/\/doi.org\/10.1038\/nrc.2016.143 (2017).","journal-title":"Nat Rev Cancer"},{"key":"33624_CR3","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1007\/s00294-019-00992-w","volume":"65","author":"E Rosonina","year":"2019","unstructured":"Rosonina, E. A conserved role for transcription factor sumoylation in binding-site selection. Curr Genet 65, 1307\u20131312. https:\/\/doi.org\/10.1007\/s00294-019-00992-w (2019).","journal-title":"Curr Genet"},{"key":"33624_CR4","doi-asserted-by":"publisher","unstructured":"Boulanger, M., Chakraborty, M., Tempe, D., Piechaczyk, M. & Bossis, G. SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies. Molecules 26, https:\/\/doi.org\/10.3390\/molecules26040828 (2021).","DOI":"10.3390\/molecules26040828"},{"key":"33624_CR5","doi-asserted-by":"publisher","first-page":"6043","DOI":"10.1093\/nar\/gkab280","volume":"49","author":"HY Ryu","year":"2021","unstructured":"Ryu, H. Y. & Hochstrasser, M. Histone sumoylation and chromatin dynamics. 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