Commitment to Myogenic Differentiation Significantly Aggravates the RNA Phenotype in Myotonic Dystrophy Type 1

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Myotonic dystrophy type 1 (DM1) is a spliceopathy caused by (CTG)n repeat expansion in the DMPK gene.
• This expansion disrupts MBNL splicing regulators, leading to aberrant alternative splicing.
• DM1 causes muscle weakness and myotonia, necessitating a deeper understanding of its effects on myogenesis.

Purpose of the Study:

• To investigate the impact of DM1 on myogenesis.
• To analyze RNA expression during the differentiation of DM1 and isogenic CRISPR/Cas9-corrected DM∆ myoblast cell lines.

Main Methods:

• Collected RNA at various myogenesis stages from DM1 and DM∆ myoblast cell lines.
• Analyzed gene expression and alternative splicing signatures using high-coverage sequencing.

Main Results:

• Proliferating myoblasts showed mild changes; however, differentiating myoblasts exhibited significant gene expression differences.
• Aberrant alternative splicing, enriched for MBNL1 motifs, aggravated during differentiation.
• Affected genes are crucial for muscle organization, contraction, and cell junctions.

Conclusions:

• Myogenesis disturbances in DM1 are most evident upon commitment to differentiation.
• MBNL1-dependent splicing plays a critical role throughout the myogenesis process in DM1.