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Natural exon skipping observed in several DMD cases can help in identifying novel therapeutic tools. Here, we show a DMD study case where the lack of a splicing factor (Celf2a), which results in exon skipping and dystrophin rescue, is due to a maternally inherited trans\u2010generational epigenetic silencing. We found that the study case and his mother express a repressive long non\u2010coding RNA, DUXAP8, whose presence correlates with silencing of the Celf2a coding region. We also demonstrate that DUXAP8 expression is lost upon cell reprogramming and that, upon induction of iPSCs into myoblasts, Celf2a expression is recovered leading to the loss of exon skipping and loss of dystrophin synthesis. Finally, CRISPR\/Cas9 inactivation of the splicing factor Celf2a was proven to ameliorate the pathological state in other DMD backgrounds establishing Celf2a ablation or inactivation as a novel therapeutic approach for the treatment of Duchenne Muscular Dystrophy.<\/jats:p>","DOI":"10.15252\/emmm.202012063","type":"journal-article","created":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T06:10:02Z","timestamp":1593411002000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Trans\u2010generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy"],"prefix":"10.1038","volume":"12","author":[{"given":"Julie","family":"Martone","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michela","family":"Lisi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Castagnetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9999-7223","authenticated-orcid":false,"given":"Alessandro","family":"Rosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerio","family":"Di Carlo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriano","family":"Setti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Mariani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessio","family":"Colantoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiziana","family":"Santini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Perone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3488-6228","authenticated-orcid":false,"given":"Luciano","family":"Di Croce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3485-8537","authenticated-orcid":false,"given":"Irene","family":"Bozzoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,6,29]]},"reference":[{"key":"BFEMMM202012063_CR1","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.celrep.2013.02.012","volume":"3","author":"S Albini","year":"2013","unstructured":"Albini S, Coutinho P, Malecova B, Giordani L, Savchenko A, Forcales SV, Puri PL (2013) Epigenetic reprogramming of human embryonic stem cells into skeletal muscle cells and generation of contractile myospheres. 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