A defective Krab-domain zinc-finger transcription factor contributes to altered myogenesis in myotonic dystrophy type 1

• Published in: Human molecular genetics 2013-12, Vol.22 (25), p.5188-5198
• Main Authors: Gauthier, Morgane, Marteyn, Antoine, Denis, Jérôme Alexandre, Cailleret, Michel, Giraud-Triboult, Karine, Aubert, Sophie, Lecuyer, Camille, Marie, Joelle, Furling, Denis, Vernet, Rémi, Yanguas, Clara, Baldeschi, Christine, Pietu, Geneviève, Peschanski, Marc, Martinat, Cécile
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Cell Line; Cell Nucleus - genetics; Cell Nucleus - metabolism; Embryonic Stem Cells; Human health and pathology; Humans; Interleukin-13 Receptor alpha1 Subunit - genetics; Interleukin-13 Receptor alpha1 Subunit - metabolism; Kruppel-Like Transcription Factors - genetics; Life Sciences; Muscle Development - genetics; Mutation; Myotonic Dystrophy - genetics; Myotonic Dystrophy - physiopathology; Signal Transduction - genetics; Tissues and Organs; Trinucleotide Repeat Expansion - genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddt373

Myotonic dystrophy type 1 (DM1) is an RNA-mediated disorder caused by a non-coding CTG repeat expansion that, in particular, provokes functional alteration of CUG-binding proteins. As a consequence, several genes with misregulated alternative splicing have been linked to clinical symptoms. In our search for additional molecular mechanisms that would trigger functional defects in DM1, we took advantage of mutant gene-carrying human embryonic stem cell lines to identify differentially expressed genes. Among the different genes found to be misregulated by DM1 mutation, one strongly downregulated gene encodes a transcription factor, ZNF37A. In this paper, we show that this defect in expression, which derives from a loss of RNA stability, is controlled by the RNA-binding protein, CUGBP1, and is associated with impaired myogenesis-a functional defect reminiscent of that observed in DM1. Loss of the ZNF37A protein results in changes in the expression of the subunit α1 of the receptor for the interleukin 13. This suggests that the pathological molecular mechanisms linking ZNF37A and myogenesis may involve the signaling pathway that is known to promote myoblast recruitment during development and regeneration.