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.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.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.doi http://dx.doi.org/10.15252/emmm.202012063
- dc.identifier.issn 1757-4676
- dc.identifier.uri http://hdl.handle.net/10230/45517
- dc.language.iso eng
- dc.publisher Wiley Open Access
- dc.relation.ispartof EMBO Mol Med. 2020; 12(8):e12063
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/855923
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-75008-P
- 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.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- 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.title Trans-generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion