title: Celf1 regulates cell cycle and is partially responsible for defective myoblast differentiation in myotonic dystrophy RNA toxicity.
abstract: 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.
authors.affiliation: The First Affiliated Hospital of Nanchang University, Nanchang 330006, China; Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Shen
authors.affiliation: The First Affiliated Hospital of Nanchang University, Nanchang 330006, China; Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Xuanying
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Liang
authors.affiliation: Stem Cell Engineering, Texas Heart Institute, Houston, TX 77030, USA.
authors.forename: Alon R
authors.initials: AR
authors.lastname: Azares
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA. Electronic address: yliu54@uh.edu.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D000067879:CELF1 Protein; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D009223:Myotonic Dystrophy / Q000235:genetics*; D065636:Myotonin-Protein Kinase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000067879:CELF1 Protein; C502743:CELF1 protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D065636:Myotonin-Protein Kinase
keywords: CUGBP1; Celf1; Differentiation; Myoblast; Myotonic dystrophy