期刊
HUMAN MOLECULAR GENETICS
卷 20, 期 1, 页码 1-15出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddq427
关键词
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资金
- National Institutes of Health [5U42RR006042-19]
- Pearson laboratory by the Canadian Institutes of Health Research
- Muscular Dystrophy Association
- Hospital for Sick Children Research Training Centre
- University of Rochester Paul Wellstone Muscular Dystrophy Cooperative Research Center
- NIH [U54NS48843]
- Cell Science Research Foundation
- Uehara Memorial Foundation
- Institut National de la Sante et de la Recherche Medicale
- Association Francaise contre les Myopathies
- Agence Nationale de la Recherche
- Ministere Francais de la Recherche et de la Technologie
- NATIONAL CENTER FOR RESEARCH RESOURCES [U42RR006042] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR049077, K24AR048143] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U54NS048843] Funding Source: NIH RePORTER
Myotonic dystrophy (DM1) affects multiple organs, shows age-dependent progression and is caused by CTG expansions at the DM1 locus. We determined the DM1 CpG methylation profile and CTG length in tissues from DM1 foetuses, DM1 adults, non-affected individuals and transgenic DM1 mice. Analysis included CTCF binding sites upstream and downstream of the CTG tract, as methylation-sensitive CTCF binding affects chromatinization and transcription of the DM1 locus. In humans, in a given foetus, expansions were largest in heart and smallest in liver, differing by 40-400 repeats; in adults, the largest expansions were in heart and cerebral cortex and smallest in cerebellum, differing by up to 5770 repeats in the same individual. Abnormal methylation was specific to the mutant allele. In DM1 adults, heart, liver and cortex showed high-to-moderate methylation levels, whereas cerebellum, kidney and skeletal muscle were devoid of methylation. Methylation decreased between foetuses and adults. Contrary to previous findings, methylation was not restricted to individuals with congenital DM1. The expanded repeat demarcates an abrupt boundary of methylation. Upstream sequences, including the CTCF site, were methylated, whereas the repeat itself and downstream sequences were not. In DM1 mice, expansion-, tissue-and age-specific methylation patterns were similar but not identical to those in DM1 individuals; notably in mice, methylation was present up-and downstream of the repeat, but greater upstream. Thus, in humans, the CpG-free expanded CTG repeat appears to maintain a highly polarized pattern of CpG methylation at the DM1 locus, which varies markedly with age and tissues.
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