Tissue- and age-specific DNA replication patterns at the CTG/CAG-expanded human myotonic dystrophy type 1 locus
Tissue- and age-specific DNA replication patterns at the CTG/CAG-expanded human myotonic dystrophy type 1 locus
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DOI：
10.1038/nsmb.1876
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发表时间：
2010-09-01
影响因子：
16.8
通讯作者：
Pearson, Christopher E.
中科院分区：
文献类型：
--
作者：
Cleary, John D.;Tome, Stephanie;Pearson, Christopher E.
强直性肌营养不良由DM1CTG/CAG重复扩张引起，患者体内不同组织和不同年龄的肌营养不良表现出不同的不稳定水平。我们测定了不同年龄的DM1转基因小鼠的患者成纤维细胞和组织中DM1基因位点的DNA复制情况，表现出不同的不稳定性。在患者细胞中，重复序列两侧有两个由CTCF位点划分的复制起始点，在扩增时复制减少。在小鼠中，扩增只从下游起点复制(CAG作为滞后模板)。在三个不同年龄的小鼠的睾丸中，针对重复序列的复制在最早的年龄暂停，在以后的年龄得到缓解--这与增加的不稳定性相一致。脑、胰腺和胸腺的复制与DM1 CTCF位点的CpG甲基化有关。根据染色质的不同，进行叉和重复序列之间的CTCF位点减少了复制。因此，不同的复制进程可能会影响特定于组织和年龄的重复序列不稳定性。
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.