The Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington's Disease
Authors
Dong, XianjunTsuji, Junko
Labadorf, Adam
Roussos, Panos
Chen, Jiang-Fan
Myers, Richard H.
Akbarian, Schahram
Weng, Zhiping
UMass Chan Affiliations
Program in Bioinformatics and Integrative BiologyDocument Type
Journal ArticlePublication Date
2015-12-04Keywords
BioinformaticsComputational Biology
Computational Neuroscience
Genetics
Molecular Genetics
Nervous System Diseases
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Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder resulting from expansion of CAG repeats in the Huntingtin (HTT) gene. Previous studies have shown mutant HTT can alter expression of genes associated with dysregulated epigenetic modifications. One of the most widely studied chromatin modifications is trimethylated lysine 4 of histone 3 (H3K4me3). Here, we conducted the first comprehensive study of H3K4me3 ChIP-sequencing in neuronal chromatin from the prefrontal cortex of six HD cases and six non-neurologic controls, and its association with gene expression measured by RNA-sequencing. We detected 2,830 differentially enriched H3K4me3 peaks between HD and controls, with 55% of them down-regulated in HD. Although H3K4me3 signals are expected to be associated with mRNA levels, we found an unexpected discordance between altered H3K4me3 peaks and mRNA levels. Gene ontology (GO) term enrichment analysis of the genes with differential H3K4me3 peaks, revealed statistically significantly enriched GO terms only in the genes with down-regulated signals in HD. The most frequently implicated biological process terms are organ morphogenesis and positive regulation of gene expression. More than 9,000 H3K4me3 peaks were located not near any recognized transcription start sites and approximately 36% of these "distal" peaks co-localized to known enhancer sites. Six transcription factors and chromatin remodelers are differentially enriched in HD H3K4me3 distal peaks, including EZH2 and SUZ12, two core subunits of the polycomb repressive complex 2 (PRC2). Moreover, PRC2 repressive state was significantly depleted in HD-enriched peaks, suggesting the epigenetic role of PRC2 inhibition associated with up-regulated H3K4me3 in Huntington's disease. In summary, our study provides new insights into transcriptional dysregulation of Huntington's disease by analyzing the differentiation of H3K4me3 enrichment.Source
PLoS One. 2015 Dec 4;10(12):e0144398. doi: 10.1371/journal.pone.0144398. eCollection 2015. Link to article on publisher's siteDOI
10.1371/journal.pone.0144398Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39883PubMed ID
26636336Related Resources
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This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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http://creativecommons.org/publicdomain/zero/1.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0144398
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Except where otherwise noted, this item's license is described as <p>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the <a href="https://creativecommons.org/publicdomain/zero/1.0/">Creative Commons CC0</a> public domain dedication.</p>