Inherited epigenetic repression of the Celf2a splicing factor mediates the amelioration of a Duchenne phenotype

Exon skipping is an effective strategy for the treatment of Duchenne Muscular Dystrophy (DMD). Natural exon skipping identified in several DMD cases can help with identifying novel therapeutic tools. Here, we demonstrate that CRISPR/Cas9 inactivation of the splicing factor Celf2a in a DMD-D44 background induces skipping of exon-45 and dystrophin rescue. Celf2a ablation could be compatible with life and curative since a DMD case with a milder symptomatology exists where exon-45 skipping occurs because of a Celf2a deficiency. We show that in this individual, Celf2a absence is due to inherited epigenetic silencing and that its repression is controlled by the lncRNA DUXAP8. ChIP-seq (8 samples) and ATAC-seq (4 samples) of WT (healthy) and GSΔ44 myoblasts (see Pubmed ID 26796035)