a novel approach to investigate tissue-specific trinucleotide repeat instability一个新颖的方法调查组织三核苷酸重复不稳定.pdfVIP

Lee et al. BMC Systems Biology 2010, 4:29 /1752-0509/4/29 RESEARCH ARTICLE Open Access A novel approach to investigate tissue-specific trinucleotide repeat instability 1* 2 2 2 2 3,6 1 Jong-Min Lee , Jie Zhang , Andrew I Su , John R Walker , Tim Wiltshire , Kihwa Kang , Ella Dragileva , 1 1 4 4 5 1 Tammy Gillis , Edith T Lopez , Marie-Josee Boily , Michel Cyr , Isaac Kohane , James F Gusella , Marcy E MacDonald1, Vanessa C Wheeler1* Abstract Background: 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. Results: 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 repeat 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 math