Open AccessTrans‐generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy
Author(s) -
Martone Julie,
Lisi Michela,
Castagnetti Francesco,
Rosa Alessandro,
Di Carlo Valerio,
Blanco Enrique,
Setti Adriano,
Mariani Davide,
Colantoni Alessio,
Santini Tiziana,
Perone Lucia,
Di Croce Luciano,
Bozzoni Irene
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012063
Subject(s) - library science , humanities , classics , biology , history , art , computer science
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 , DUXAP 8, whose presence correlates with silencing of the Celf2a coding region. We also demonstrate that DUXAP 8 expression is lost upon cell reprogramming and that, upon induction of iPSC s 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.