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Trans-generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy

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dc.contributor.author Martone, Julie
dc.contributor.author Lisi, Michela
dc.contributor.author Castagnetti, Francesco
dc.contributor.author Rosa, Alessandro
dc.contributor.author Di Carlo, Valerio
dc.contributor.author Blanco, Enrique
dc.contributor.author Setti, Adriano
dc.contributor.author Mariani, Davide
dc.contributor.author Colantoni, Alessio
dc.contributor.author Santini, Tiziana
dc.contributor.author Perone, Lucia
dc.contributor.author Di Croce, Luciano
dc.contributor.author Bozzoni, Irene
dc.date.accessioned 2020-10-20T06:01:56Z
dc.date.available 2020-10-20T06:01:56Z
dc.date.issued 2020
dc.identifier.citation Martone J, Lisi M, Castagnetti F, Rosa A, Di Carlo V, Blanco E, Setti A, Mariani D, Colantoni A, Santini T, Perone L, Di Croce L, Bozzoni I. Trans-generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy. EMBO Mol Med. 2020; 12(8):e12063. DOI: 10.15252/emmm.202012063
dc.identifier.issn 1757-4676
dc.identifier.uri http://hdl.handle.net/10230/45517
dc.description.abstract Exon skipping is an effective strategy for the treatment of many Duchenne Muscular Dystrophy (DMD) mutations. 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-generational epigenetic silencing. We found that the study case and his mother express a repressive long non-coding 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.
dc.description.sponsorship This work was partially supported by grants from ERC‐2019‐SyG (855923‐ASTRA), Telethon (GGP16213), Parent Project Italia, AIRC (IG 2019 Id. 23053) and PRIN 2017 (2017P352Z4) to I.B.; Spanish Ministry of Economy, Industry and Competitiveness (MEIC) (BFU2016‐75008‐P) to L.D.C. and Sapienza Research Calls (RM118164363B1D21) to J.M.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Wiley Open Access
dc.relation.ispartof EMBO Mol Med. 2020; 12(8):e12063
dc.rights © 2020 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Trans-generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.15252/emmm.202012063
dc.subject.keyword ATAC sequencing
dc.subject.keyword DMD Exon skipping
dc.subject.keyword iPSC Reprogramming
dc.subject.keyword lncRNAs
dc.subject.keyword Trans-generational epigenetic inheritance
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/855923
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-75008-P
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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