Genomics

Dataset Information

297

H3K4me3 modification profiling of Huntingtons disease and control human post-mortem prefrontal cortex brain samples


ABSTRACT: Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder resulting from expansion in the number of CAG repeats in the coding region of exon 1 of the Huntingtin (HTT) gene. 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. We examined two classes of H3K4me3 peaks; those located near transcription start sites (TSSs) (termed “proximal”) and those located distantly from TSSs (termed “distal”). We detected 2,830 differentially enriched H3K4me3 peaks between HD and controls, with 55% of them down regulated in HD. We found an unexpected discordance between levels of H3K4me3 and mRNA, with H3K4me3 predominantly reduced in HD and mRNA predominantly increased in HD. Gene ontology (GO) term enrichment analysis of the genes associated with the proximally positioned peaks, revealed diverse biological process terms with organ morphogenesis and positive regulation of gene expression most frequently implicated. GO terms relating to transcription and the extracellular matrix were also observed. Approximately 36% of the distal peaks co-localized to enhancer sites, with six transcription factors and chromatin remodelers differentially enriched in HD H3K4me3 distal peaks, including EZH2 and SUZ12, two core subunits of the polycomb repressive complex 2 (PRC2). Moreover, sequences repressed by polycomb in normal frontal cortex were significantly depleted in HD-enriched peaks, suggesting that H3K4me3 histone hypermethylation is linked to dysregulated polycomb activity in the HD neuronal epigenome. 12 H3K4me3 ChIP-seq libraries (6 Huntington's disease, 6 neurologically normal control), and 1 input DNA library (neurologically normal control)

ORGANISM(S): Homo sapiens  

SUBMITTER: Jiang-Fan Chen   Xianjun Dong  Schahram Akbarian  Junko Tsuji  Panos Roussos  Richard H Myers  Zhiping Weng  Adam Labadorf 

PROVIDER: E-GEOD-68952 | ArrayExpress | 2015-12-14

SECONDARY ACCESSION(S): GSE68952SRP058390PRJNA284153

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

The Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington's Disease.

Dong Xianjun X   Tsuji Junko J   Labadorf Adam A   Roussos Panos P   Chen Jiang-Fan JF   Myers Richard H RH   Akbarian Schahram S   Weng Zhiping Z  

PloS one 20151204 12


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 corte  ...[more]

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