Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline.

Détails

ID Serval
serval:BIB_C3E7A19EDBF9
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline.
Périodique
Human Molecular Genetics
Auteur(s)
Dion V., Lin Y., Hubert L., Waterland R.A., Wilson J.H.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Statut éditorial
Publié
Date de publication
2008
Volume
17
Numéro
9
Pages
1306-1317
Langue
anglais
Résumé
Expanded CAG repeat tracts are the cause of at least a dozen neurodegenerative disorders. In humans, long CAG repeats tend to expand during transmissions from parent to offspring, leading to an earlier age of disease onset and more severe symptoms in subsequent generations. Here, we show that the maintenance DNA methyltransferase Dnmt1, which preserves the patterns of CpG methylation, plays a key role in CAG repeat instability in human cells and in the male and female mouse germlines. SiRNA knockdown of Dnmt1 in human cells destabilized CAG triplet repeats, and Dnmt1 deficiency in mice promoted intergenerational expansion of CAG repeats at the murine spinocerebellar ataxia type 1 (Sca1) locus. Importantly, Dnmt1(+/-) SCA1 mice, unlike their Dnmt1(+/+) SCA1 counterparts, closely reproduced the intergenerational instability patterns observed in human SCA1 patients. In addition, we found aberrant DNA and histone methylation at sites within the CpG island that abuts the expanded repeat tract in Dnmt1-deficient mice. These studies suggest that local chromatin structure may play a role in triplet repeat instability. These results are consistent with normal epigenetic changes during germline development contributing to intergenerational instability of CAG repeats in mice and in humans.
Mots-clé
Age Factors, Animals, Cell Line, Cell Line, Tumor, Chromatin Immunoprecipitation, DNA (Cytosine-5-)-Methyltransferase/genetics, DNA (Cytosine-5-)-Methyltransferase/metabolism, DNA Methylation, DNA-Binding Proteins/genetics, DNA-Binding Proteins/metabolism, Female, Genomic Instability, Genotype, Germ-Line Mutation, Histones/metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Ovary/metabolism, RNA Interference, RNA, Small Interfering/genetics, Spinocerebellar Ataxias/genetics, Testis/metabolism, Transcription, Genetic, Trinucleotide Repeat Expansion
Pubmed
Web of science
Open Access
Oui
Création de la notice
12/02/2014 17:20
Dernière modification de la notice
09/05/2019 0:54
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