title: Myotonic dystrophy type 1 patient-derived iPSCs for the investigation of CTG repeat instability.
abstract: Myotonic dystrophy type 1 (DM1) is an autosomal-dominant multi-system disease caused by expanded CTG repeats in dystrophia myotonica protein kinase (DMPK). The expanded CTG repeats are unstable and can increase the length of the gene with age, which worsens the symptoms. In order to establish a human stem cell system suitable for the investigation of repeat instability, DM1 patient-derived iPSCs were generated and differentiated into three cell types commonly affected in DM1, namely cardiomyocytes, neurons and myocytes. Then we precisely analysed the CTG repeat lengths in these cells. Our DM1-iPSCs showed a gradual lengthening of CTG repeats with unchanged repeat distribution in all cell lines depending on the passage numbers of undifferentiated cells. However, the average CTG repeat length did not change significantly after differentiation into different somatic cell types. We also evaluated the chromatin accessibility in DM1-iPSCs using ATAC-seq. The chromatin status in DM1 cardiomyocytes was closed at the DMPK locus as well as at SIX5 and its promoter region, whereas it was open in control, suggesting that the epigenetic modifications may be related to the CTG repeat expansion in DM1. These findings may help clarify the role of repeat instability in the CTG repeat expansion in DM1.
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.|Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Ueki
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamori
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Morizane
authors.affiliation: Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kamon
authors.affiliation: Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Araki
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.|Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Masanori P
authors.initials: MP
authors.lastname: Takahashi
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Sakurai
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D042822:Genomic Instability; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D059785:Karyotype; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D012326:RNA Splicing; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats