RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression
Authors
Labadorf, AdamHoss, Andrew
Lagomarsino, Valentina
Latourelle, Jeanne C.
Hadzi, Tiffany C.
Bregu, Joli
MacDonald, Marcy E.
Gusella, James F.
Chen, Jiang-Fan
Akbarian, Schahram
Weng, Zhiping
Myers, Richard H.
UMass Chan Affiliations
Program in Bioinformatics and Integrative BiologyDocument Type
Journal ArticlePublication Date
2015-12-04Keywords
BioinformaticsComputational Biology
Computational Neuroscience
Developmental Biology
Developmental Neuroscience
Genetics
Nervous System Diseases
Neurology
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Show full item recordAbstract
Huntington's Disease (HD) is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing. Surprisingly, 19% (5,480) of the 28,087 confidently detected genes are differentially expressed (FDR < 0.05) and are predominantly up-regulated. A novel hypothesis-free geneset enrichment method that dissects large gene lists into functionally and transcriptionally related groups discovers that the differentially expressed genes are enriched for immune response, neuroinflammation, and developmental genes. Markers for all major brain cell types are observed, suggesting that HD invokes a systemic response in the brain area studied. Unexpectedly, the most strongly differentially expressed genes are a homeotic gene set (represented by Hox and other homeobox genes), that are almost exclusively expressed in HD, a profile not widely implicated in HD pathogenesis. The significance of transcriptional changes of developmental processes in the HD brain is poorly understood and warrants further investigation. The role of inflammation and the significance of non-neuronal involvement in HD pathogenesis suggest anti-inflammatory therapeutics may offer important opportunities in treating HD.Source
PLoS One. 2015 Dec 4;10(12):e0143563. doi: 10.1371/journal.pone.0143563. eCollection 2015. Link to article on publisher's siteDOI
10.1371/journal.pone.0143563Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39882PubMed ID
26636579Related Resources
Link to Article in PubMedRights
Copyright: 2015 Labadorf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0143563
Scopus Count
Except where otherwise noted, this item's license is described as <p>Copyright: 2015 Labadorf et al. This is an open access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited</p>