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Analyzing RNA sequencing data from muscle biopsies of patients with FSHD and Smchd1 knocked out cells, we found mis-splicing of hundreds of genes upon SMCHD1 loss. We conducted a high-throughput screen of splicing factors, revealing the involvement of the splicing factor RBM5 in the mis-splicing of DNMT3B. Subsequent RNA immunoprecipitation experiments confirmed that SMCHD1 is required for RBM5 recruitment. Last, we show that mis-splicing of DNMT3B leads to hypomethylation of the D4Z4 region and to DUX4 overexpression. These results suggest that DNMT3B mis-splicing due to SMCHD1 loss plays a major role in FSHD pathogenesis.<\/jats:p>","DOI":"10.1126\/sciadv.adn7732","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T13:58:57Z","timestamp":1716991137000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":11,"title":["DNMT3B splicing dysregulation mediated by SMCHD1 loss contributes to DUX4 overexpression and FSHD pathogenesis"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4353-6521","authenticated-orcid":true,"given":"Eden","family":"Engal","sequence":"first","affiliation":[{"name":"The Lautenberg Center for Immunology and Cancer Research, The Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel."},{"name":"Department of Biochemistry and Molecular Biology, The Institute for Medical Research 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