While missing a gym class can happen from time to time without leaving you feeling too guilty (!), you really shouldn’t “skip” a fascinating new study that now describes how a maternally-transmitted epigenetic “exon skipping” effect may act as the foundation for new therapeutic approaches for a devastating genetic muscle-weakening disease.
A majority of Duchenne muscular dystrophy (DMD)-associated mutations in the dystrophin gene lead to the formation of premature termination codons that impair mRNA translation, protein production, and hence problems with the body’s musculature; however, induced exon skipping can allow for the production of truncated dystrophin mRNA and protein that reduces DMD-associated symptoms.
Interestingly, a crew of researchers skippered by Irene Bozzoni (Sapienza University of Rome, Italy) reported one example of natural exon skipping in a DMD patient. In this case study, an inherent lack of the CELF2A splicing enhancer protein in a male patient induced natural exon skipping and rescued dystrophin protein expression. Not wishing to skip a beat, the author’s follow-up study now reports that the loss of CELF2A in this DMD patient derives from a maternally-transmitted intergenerational epigenetic silencing effect that involves the expression of a repressive long non‐coding RNA (lncRNA).
So, let’s not skip any of the details from this unmissable new study from Martone, Lisi, and Castagnetti and Colleagues:
- Genetic mutation doesn’t drive the absence of CELF2A expression in this case study
- Instead, a maternally-transmitted intergenerational epigenetic silencing effect involving the expression of the DUXAP8 repressive lncRNA represses CELF2A expression
- Both the patient and his mother express DUXAP8 and display CELF2A silencing
- The differentiation of induced pluripotent stem cells (iPSCs) derived from fibroblasts isolated from both the patient and his mother into myocytes leads to the loss of DUXAP8 expression, re-expression of CELF2A, and a reversal of exon skipping
- This finding confirms the regulation of CELF2A expression and resulting exon skipping at the epigenetic level
- The induced loss of DUXAP8 expression in patient myoblasts by RNA interference prompts CELF2A expression, while overexpression of DUXAP8 in control myoblasts represses CELF2A expression
- Finally, the team highlights the general applicability of CELF2A ablation/CELF2A inactivation as a therapeutic approach to DMD
- CRISPR/Cas9-mediated inactivation of CELF2A in two unrelated iPSC lines derived from DMA patients with different mutations led to exon skipping and the partial rescue of the dystrophin production following the induction of muscle differentiation
Let’s now skip over to the future research discussed by the authors – they hope to next decipher how DUXAP8 affects CELF2A transcription, and note that the location of DUXAP8 close to the centromere, which is known to display repeat sequences and repressive epigenetic modifications that may play a role.
Senior author Irene Bozzoni shares, “We saw that even in the young man’s mother, the gene that produces the protein was inactivated and that the lack of expression of Celf2a is not due to mutations of its gene, but to epigenetic silencing that operates through a specific non-coding RNA. The real goal would be to reproduce this specific molecular condition in other patients, opening important new perspectives for treatment”.
So don’t skip over this new study that may lay the groundwork for new and practical therapeutic approaches for a significant subgroup of DMD patients – check out all the details at EMBO Molecular Medicine, June 2020.