A novel approach to investigate tissue-specific trinucleotide repeat instability

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-specifi...

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Autores principales: Lee, Jong-Min, Zhang, Jie, Su, Andrew I, Walker, John R, Wiltshire, Tim, Kang, Kihwa, Dragileva, Ella, Gillis, Tammy, Lopez, Edith T, Boily, Marie-Josee, Cyr, Michel, Kohane, Isaac, Gusella, James F, MacDonald, Marcy E, Wheeler, Vanessa C
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856555/
https://www.ncbi.nlm.nih.gov/pubmed/20302627
http://dx.doi.org/10.1186/1752-0509-4-29
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author Lee, Jong-Min
Zhang, Jie
Su, Andrew I
Walker, John R
Wiltshire, Tim
Kang, Kihwa
Dragileva, Ella
Gillis, Tammy
Lopez, Edith T
Boily, Marie-Josee
Cyr, Michel
Kohane, Isaac
Gusella, James F
MacDonald, Marcy E
Wheeler, Vanessa C
author_facet Lee, Jong-Min
Zhang, Jie
Su, Andrew I
Walker, John R
Wiltshire, Tim
Kang, Kihwa
Dragileva, Ella
Gillis, Tammy
Lopez, Edith T
Boily, Marie-Josee
Cyr, Michel
Kohane, Isaac
Gusella, James F
MacDonald, Marcy E
Wheeler, Vanessa C
author_sort Lee, Jong-Min
collection PubMed
description 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 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. CONCLUSION: 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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spelling pubmed-28565552010-04-20 A novel approach to investigate tissue-specific trinucleotide repeat instability Lee, Jong-Min Zhang, Jie Su, Andrew I Walker, John R Wiltshire, Tim Kang, Kihwa Dragileva, Ella Gillis, Tammy Lopez, Edith T Boily, Marie-Josee Cyr, Michel Kohane, Isaac Gusella, James F MacDonald, Marcy E Wheeler, Vanessa C BMC Syst Biol Research article 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 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. CONCLUSION: 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. BioMed Central 2010-03-19 /pmc/articles/PMC2856555/ /pubmed/20302627 http://dx.doi.org/10.1186/1752-0509-4-29 Text en Copyright ©2010 Lee et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research article
Lee, Jong-Min
Zhang, Jie
Su, Andrew I
Walker, John R
Wiltshire, Tim
Kang, Kihwa
Dragileva, Ella
Gillis, Tammy
Lopez, Edith T
Boily, Marie-Josee
Cyr, Michel
Kohane, Isaac
Gusella, James F
MacDonald, Marcy E
Wheeler, Vanessa C
A novel approach to investigate tissue-specific trinucleotide repeat instability
title A novel approach to investigate tissue-specific trinucleotide repeat instability
title_full A novel approach to investigate tissue-specific trinucleotide repeat instability
title_fullStr A novel approach to investigate tissue-specific trinucleotide repeat instability
title_full_unstemmed A novel approach to investigate tissue-specific trinucleotide repeat instability
title_short A novel approach to investigate tissue-specific trinucleotide repeat instability
title_sort novel approach to investigate tissue-specific trinucleotide repeat instability
topic Research article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856555/
https://www.ncbi.nlm.nih.gov/pubmed/20302627
http://dx.doi.org/10.1186/1752-0509-4-29
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