title: Tissue- and age-specific DNA replication patterns at the CTG/CAG-expanded human myotonic dystrophy type 1 locus.
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.
authors: Program of Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: John D
authors: JD
authors: Cleary
authors: Stéphanie
authors: S
authors: Tomé
authors: Arturo
authors: A
authors: López Castel
authors: Gagan B
authors: GB
authors: Panigrahi
authors: Laurent
authors: L
authors: Foiry
authors: Katharine A
authors: KA
authors: Hagerman
authors: Hana
authors: H
authors: Sroka
authors: David
authors: D
authors: Chitayat
authors: Geneviève
authors: G
authors: Gourdon
authors: Christopher E
authors: CE
authors: Pearson
mesh_terms: D000375:Aging; D000818:Animals; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D002888:Chromosomes, Human, Pair 19; D018899:CpG Islands; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D004261:DNA Replication; D056426:Genetic Loci; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism*; D009928:Organ Specificity; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D012097:Repressor Proteins; D004247:DNA