1. Tissue- and age-specific DNA replication patterns at the CTG/CAG-expanded human myotonic dystrophy type 1 locus.
- Author
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Cleary JD, Tomé S, López Castel A, Panigrahi GB, Foiry L, Hagerman KA, Sroka H, Chitayat D, Gourdon G, and Pearson CE
- Subjects
- Animals, Binding Sites, CCCTC-Binding Factor, Chromosomes, Human, Pair 19, CpG Islands, DNA Methylation, Genetic Loci, Humans, Mice, Mice, Transgenic, Organ Specificity, Repressor Proteins metabolism, Aging, DNA metabolism, DNA Replication, Myotonic Dystrophy genetics, Myotonic Dystrophy metabolism
- Abstract
Myotonic dystrophy, caused by DM1 CTG/CAG repeat expansions, shows varying instability levels between tissues and across ages within patients. We determined DNA replication profiles at the DM1 locus in patient fibroblasts and tissues from DM1 transgenic mice of various ages showing different instability. In patient cells, the repeat is flanked by two replication origins demarcated by CTCF sites, with replication diminished at the expansion. In mice, the expansion replicated from only the downstream origin (CAG as lagging template). In testes from mice of three different ages, replication toward the repeat paused at the earliest age and was relieved at later ages-coinciding with increased instability. Brain, pancreas and thymus replication varied with CpG methylation at DM1 CTCF sites. CTCF sites between progressing forks and repeats reduced replication depending on chromatin. Thus, varying replication progression may affect tissue- and age-specific repeat instability.
- Published
- 2010
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