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| Status |
Public on Apr 01, 2011 |
| Title |
A novel approach to investigate tissue-specific trinucleotide repeat instability |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
In Huntington’s disease (HD), an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD CAG repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in the striatum, suggesting that tissue-specific CAG length changes could modify the disease process. Therefore, understanding the mechanisms underlying the tissue specificity of somatic instability may provide novel routes to therapies. However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors.
Here we describe a novel approach to gain insight into the factors responsible for the tissue specificity of somatic instability. Using accurate genetic knock-in mouse models of HD, we developed a reliable, high-throughput method to quantify tissue HD CAG instability and integrated this with genome-wide bioinformatic approaches. Using tissue instability quantified in 16 tissues as a phenotype and tissue microarray gene expression as a predictor, we built a mathematical model and identified a gene expression signature that accurately predicted tissue instability. Using the predictive ability of this signature we found that somatic instability was not a consequence of pathogenesis. In support of this, genetic crosses with models of accelerated neuropathology failed to induce somatic instability. In addition, we searched for genes and pathways that correlated with tissue instability. We found that expression levels of DNA repair genes did not explain the tissue specificity of somatic instability. Instead, our data implicate other pathways, particularly cell cycle, metabolism and neurotransmitter pathways, acting in combination to generate tissue-specific patterns of instability.
Our study clearly demonstrates that multiple tissue factors reflect the level of somatic instability in different tissues. In addition, our quantitative, genome-wide approach is readily applicable to high-throughput assays and opens the door to widespread applications with the potential to accelerate the discovery of drugs that alter tissue instability.
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| Overall design |
Mouse striatum and cerebellum, 10 weeks old, Affymetrix MG430 2.0 arrays, gcRMA.
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| Contributor(s) |
Lee J, MacDonald ME |
| Citation(s) |
20302627 |
| Submission date |
Jan 07, 2010 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Jong-Min Lee |
| E-mail(s) |
jlee51@partners.org
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| Phone |
617-726-5726
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| Organization name |
Massachusetts General Hospital
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| Department |
Center for Human Genetic Reseaarch
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| Street address |
185 Cambridge Street
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02114 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (12)
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| GSM229435 |
Hdh+/Hdh+ striatum at 3~10 weeks biological rep 4 |
| GSM229436 |
Hdh+/Hdh+ striatum at 3~10 weeks biological rep 5 |
| GSM229437 |
Hdh+/Hdh+ striatum at 3~10 weeks biological rep 6 |
| GSM229438 |
HdhQ111/HdhQ111 striatum at 3~10 weeks biological rep 4 |
| GSM229439 |
HdhQ111/HdhQ111 striatum at 3~10 weeks biological rep 5 |
| GSM229440 |
HdhQ111/HdhQ111 striatum at 3~10 weeks biological rep 6 |
| GSM229456 |
Hdh+/Hdh+ cerebellum at 3~10 weeks biological rep 4 |
| GSM229457 |
Hdh+/Hdh+ cerebellum at 3~10 weeks biological rep 5 |
| GSM229458 |
Hdh+/Hdh+ cerebellum at 3~10 weeks biological rep 6 |
| GSM229459 |
HdhQ111/HdhQ111 cerebellum at 3~10 weeks biological rep 4 |
| GSM229460 |
HdhQ111/HdhQ111 cerebellum at 3~10 weeks biological rep 5 |
| GSM229461 |
HdhQ111/HdhQ111 cerebellum at 3~10 weeks biological rep 6 |
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| Relations |
| BioProject |
PRJNA121867 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE19780_RAW.tar |
45.4 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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