Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, USDA Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2008; 17(9):1306-17. DOI: 10.1093/hmg/ddn019
Source: PubMed


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.

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    • "While depletion of proteins that cause transcriptional silencing or treatment with small molecule inhibitors of such proteins do affect repeat expansion in different ways [42] [43] [44] [45], the reported effect is not thought to be mediated by a change in the chromatin or transcriptional activity of the repeat-containing sequence [42] [45]. Nonetheless, there is evidence from a number of different systems suggesting that transcription through the repeat is important for expansion. "
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    • "Many expandable repeats are near CpG islands, and several studies correlate changes in DNA methylation with repeat stability. For example, inhibition of DNA methylation increased expansions at the CTG tract in the DMPK locus in DM1 patient cells (Gorbunova et al., 2004), and deficiency of DNA methyltransferase Dnmt1 increased germ-line but not somatic expansions in a SCA1 mouse model (Dion et al., 2008). The effect of the Dnmt1 deficiency was not mediated by an increase in transcription through the repeat or by many genes thought to be important for expansion; therefore, a different aspect of the chromatin structure influenced by methylation may contribute to expansion propensity. "
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    • "Trinucleotide repeat expansions are involved in at least two dozens dramatic neurological and developmental disorders in human [1], [2], [3], [4], [5]. A large amount of studies were devoted to understanding the mechanisms responsible for large CAG/CTG repeat expansions, using model systems as diverse as bacteria [6], [7], yeast [8], [9], [10], drosophila [11], mice [12], [13], [14], [15] or human cell lines [16], [17], [18]. Over the last 20 years or so, it was demonstrated that replication slippage, double-strand break repair, base excision repair, nucleotide excision repair, mismatch repair, basically any mechanism involving de novo DNA synthesis within CAG/CTG triplet repeats would favor repeat size changes (reviewed in: [1], [19], [20], [21]. "
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