Trans-generational Epigenetic Regulation Associated with the Amelioration of Duchenne Muscular Dystrophy

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2020 Jun 30

PMID 32596946

Citations 6

Authors

Julie Martone

Michela Lisi

Francesco Castagnetti

Alessandro Rosa

Valerio Di Carlo

Enrique Blanco

Adriano Setti

Davide Mariani

Alessio Colantoni

Tiziana Santini

Lucia Perone

Luciano Di Croce

Irene Bozzoni

Affiliations

Soon will be listed here.

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.

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