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dc.contributor.authorDong, Xianjun
dc.contributor.authorTsuji, Junko
dc.contributor.authorLabadorf, Adam
dc.contributor.authorRoussos, Panos
dc.contributor.authorChen, Jiang-Fan
dc.contributor.authorMyers, Richard H.
dc.contributor.authorAkbarian, Schahram
dc.contributor.authorWeng, Zhiping
dc.date2022-08-11T08:09:44.000
dc.date.accessioned2022-08-23T16:41:26Z
dc.date.available2022-08-23T16:41:26Z
dc.date.issued2015-12-04
dc.date.submitted2016-01-15
dc.identifier.citationPLoS One. 2015 Dec 4;10(12):e0144398. doi: 10.1371/journal.pone.0144398. eCollection 2015. <a href="http://dx.doi.org/10.1371/journal.pone.0144398">Link to article on publisher's site</a>
dc.identifier.issn1932-6203 (Linking)
dc.identifier.doi10.1371/journal.pone.0144398
dc.identifier.pmid26636336
dc.identifier.urihttp://hdl.handle.net/20.500.14038/39883
dc.description.abstractHuntington'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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26636336&dopt=Abstract">Link to Article in PubMed</a>
dc.rights<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>
dc.rights.urihttp://creativecommons.org/publicdomain/zero/1.0/
dc.subjectBioinformatics
dc.subjectComputational Biology
dc.subjectComputational Neuroscience
dc.subjectGenetics
dc.subjectMolecular Genetics
dc.subjectNervous System Diseases
dc.titleThe Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington's Disease
dc.typeJournal Article
dc.source.journaltitlePloS one
dc.source.volume10
dc.source.issue12
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3689&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2685
dc.identifier.contextkey8015338
refterms.dateFOA2022-08-23T16:41:26Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/2685
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.source.pagese0144398


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<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>
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>