title: Regulation of the promoter of CUG triplet repeat binding protein, Cugbp1, during myogenesis.
abstract: CUG triplet repeat binding protein, CUGBP1, plays a critical role in the development of skeletal muscle pathology in patients with Myotonic Dystrophy 1 (DM1). In this paper, we have characterized transcriptional regulation of mouse Cugbp1 gene during normal myogenesis. There are several Cugbp1 mRNA species with variable 5' ends. We found that these mRNA species have different patterns of expression during myogenesis. Isoforms 1 and 2 are mainly expressed in myotubes, while expression of isoform 3 is increased during transition of myoblasts to myotubes and during transition of myotubes to myofibers. We have cloned a short region of the Cugbp1 promoter, which is responsible for the regulation of the isoform 3, and have identified within this region three different transcription start sites. This promoter region exhibits high activity in myoblasts and the activity of this region is significantly increased in myotubes. The Cugbp1 promoter contains three E-box elements. A mutation of one of the E-boxes, E(3), significantly reduces activity of the Cugbp1 promoter. Gelshift and ChIP assays showed that E(3)-box is occupied by E12, CBP and p300 proteins in myoblasts, while in differentiated myotubes this element is occupied by myogenin, E12 and p300. The binding of myogenin to the Cugbp1 promoter correlates with activation of the promoter during differentiation. Our data show that myogenin is a key regulator of the Cugbp1 promoter since overexpression of myogenin increases the activity of the Cugbp1 promoter; while the inhibition of myogenin reduces activity of the Cugbp1 promoter. These data show that transcription of Cugbp1 gene in muscle is regulated by myogenin and E proteins and suggest that the co-operation of several transcription factors is important for the activation of the Cugbp1 promoter.
authors.affiliation: Department of Medicine, Section of Cardiovascular Sciences, Baylor College of Medicine, One Baylor Plaza, Houston Texas 77030, USA.
authors.forename: Claudia H
authors.initials: CH
authors.lastname: Huichalaf
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.forename: Guo-Li
authors.initials: GL
authors.lastname: Wang
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Timchenko
authors.forename: Lubov
authors.initials: L
authors.lastname: Timchenko
mesh_terms: D000818:Animals; D001483:Base Sequence; D000067879:CELF1 Protein; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000378:metabolism; D018008:Myogenin / Q000737:chemistry* / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D014158:Transcription, Genetic; D018911:Trinucleotide Repeats
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; D018008:Myogenin; D020033:Protein Isoforms; D016601:RNA-Binding Proteins