Celf1 regulates cell cycle and is partially responsible for defective myoblast differentiation in myotonic dystrophy RNA toxicity

• Published in: Biochimica et biophysica acta 2015-07, Vol.1852 (7), p.1490-1497
• Main Authors: Peng, Xiaoping, Shen, Xiaopeng, Chen, Xuanying, Liang, Rui, Azares, Alon R., Liu, Yu
• Format: Article
• Language: English
• Subjects: Animals; Celf1; CELF1 Protein; Cell Cycle; Cell Differentiation; Cell Line; CUGBP1; Differentiation; Mice; Myoblast; Myoblasts - cytology; Myoblasts - metabolism; Myotonic dystrophy; Myotonic Dystrophy - genetics; Myotonin-Protein Kinase - genetics; Myotonin-Protein Kinase - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2015.04.010

Myotonic dystrophy is a neuromuscular disease of RNA toxicity. The disease gene DMPK harbors expanded CTG trinucleotide repeats on its 3′-UTR. The transcripts of this mutant DMPK led to misregulation of RNA-binding proteins including MBNL1 and Celf1. In myoblasts, CUG-expansion impaired terminal differentiation. In this study, we formally tested how the abundance of Celf1 regulates normal myocyte differentiation, and how Celf1 expression level mediates CUG-expansion RNA toxicity-triggered impairment of myocyte differentiation. As the results, overexpression of Celf1 largely recapitulated the defects of myocytes with CUG-expansion, by increasing myocyte cycling. Knockdown of endogenous Celf1 level led to precocious myotube formation, supporting a negative connection between Celf1 abundance and myocyte terminal differentiation. Finally, knockdown of Celf1 in myocyte with CUG-expansion led to partial rescue, by promoting cell cycle exit. Our results suggest that Celf1 plays a distinctive and negative role in terminal myocyte differentiation, which partially contribute to DM1 RNA toxicity. Targeting Celf1 may be a valid strategy in correcting DM1 muscle phenotypes, especially for congenital cases. •3′-UTR CUG trinucleotide repeat expansion leads to accelerated myoblast cycling.•Celf1 upregulation by CUG-expansion is responsible for accelerated myoblast cycling.•Inhibition of Celf1 leads to precocious myoblast differentiation.•Celf1 contributes little to alternative splicing patterns in myoblasts.