Myotonic dystrophy type 1 embryonic stem cells show decreased myogenic potential, increased CpG methylation at the DMPK locus and RNA mis-splicing
Silvie Franck,
Edouard Couvreu De Deckersberg,
Jodi L. Bubenik,
Christina Markouli,
Lise Barbé,
Joke Allemeersch,
Pierre Hilven,
Geoffrey Duqué,
Maurice S. Swanson,
Alexander Gheldof,
Claudia Spits,
D. Karen
Affiliations
Silvie Franck
Department Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium
Edouard Couvreu De Deckersberg
Department Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium
Jodi L. Bubenik
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
Christina Markouli
Department Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium
Lise Barbé
Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, 94107 CA, United States
Joke Allemeersch
Genomics Core, UZ Leuven, Leuven 3000, Belgium
Pierre Hilven
Department Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium
Geoffrey Duqué
Department Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium
Maurice S. Swanson
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
Alexander Gheldof
Department Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium
Claudia Spits
Department Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium
D. Karen
Department Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium
Skeletal muscle tissue is severely affected in myotonic dystrophy type 1 (DM1) patients, characterised by muscle weakness, myotonia and muscle immaturity in the most severe congenital form of the disease. Previously, it was not known at what stage during myogenesis the DM1 phenotype appears. In this study we differentiated healthy and DM1 human embryonic stem cells to myoblasts and myotubes and compared their differentiation potential using a comprehensive multi-omics approach. We found myogenesis in DM1 cells to be abnormal with altered myotube generation compared to healthy cells. We did not find differentially expressed genes between DM1 and non-DM1 cell lines within the same developmental stage. However, during differentiation we observed an aberrant inflammatory response and increased CpG methylation upstream of the CTG repeat at the myoblast level and RNA mis-splicing at the myotube stage. We show that early myogenesis modelled in hESC reiterates the early developmental manifestation of DM1.
