|Waterland, Robert - Rob|
Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/15/2008
Publication Date: 5/1/2008
Citation: Dion, V., Lin, Y., Hubert Jr., L., Waterland, R.A., Wilson, J.H. 2008. Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline. Human Molecular Genetics. 17(9):1306-1317. Interpretive Summary: Triplet repeat instability describes a phenomenon in the genome in which certain regions of DNA contain tracts of repeating 'triplets' of nucleotides (for example, a CAG repeat tract would look like CAGCAGCAGCAG...). These repeat tracts can undergo expansion (increase in the number of repeats), which is associated with over a dozen neurological diseases. We investigated the molecular mechanism of triplet repeat instability, and obtained data indicating that DNA methylation (a chemical modification of DNA that regulates how genes are expressed) plays a role in triplet repeat expansion.
Technical Abstract: 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.