Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

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

ABSTRACT: Huntingtonâs 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 âproximalâ) and those located distantly from TSSs (termed âdistalâ). 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: Zhiping Weng

PROVIDER: E-GEOD-68952 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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]

PMID: 26636336

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Project description:In order to identify epigenetic protein complexes recruited to histone PTMs in the deadly human malaria parasite Plasmodium falciparum, we set out to perform histone peptide pulldowns with various histone peptides. Biotinylated peptides corresponding to P. falciparum histone variant H2A.Z, H2B.Z and H3.3, canonical P. falciparum histone H4 or human histone H4 tail sequences (differing on position 21 from the P. falciparum peptide) bearing multiple histone post-translational modifications (acetylations and/or methylations) as well as the unmodified control peptides were coupled to beads and incubated with native nuclear extract obtained from mixed-stage asexual cultures. Proteins preferentially binding to the modified histone peptide were identified by quantitative proteomics using di-methyl labelling. This yielded 6 out of 7 P. falciparum bromo-domain proteins preferentially binding to the acetylated histone peptides, as well as many putative bromo-domain protein interactors. In addition, a PHD-domain containing protein was found to be recruiting a PfSAGA-like complex to H3K4 di- and tri-methylated peptides. 7 reader-domain containing proteins (BDP1, BDP2, BDP4, TAF1, GCN5, PHD1, PHD2) and 5 putative interactors (PF3D7_0306100, PF3D7_1124300, PF3D7_1128000, PF3D7_1225200, PF3D7_1451200) were endogenously tagged by GFP or HA and used in quantitative GFP-/HA-IP-MS/MS experiments to further characterize epigenetic reader-complex composition. As negative control, GFP- and HA-IPs were performed on native nuclear extract not encoding tagged protein. Most HPP experiment employed a 3-label setup, while few only relied on “light” and “heavy”-label sample pools (labels and conditions listed below). GFP- and HA-IP experiments were using a 2-label “light” and “heavy” di-methyl setup only. For all experiments technical replicates were performed using a label-swap approach (called F (forward) and R (reverse)) and independent biological replicates were performed for each. For GFP- and HA-IP forward reactions are set-up as: GFP-/HA-beads = “heavy” di-methyl label, control-beads = “light” di-methyl label. Reverse reactions are set-up as: GFP-/HA-beads = “light” di-methyl label, control-beads = “heavy” di-methyl label. For GFP-/HA-IP raw files the bait and tag used for fishing are included in the file name.

Dataset Information

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

Publications

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

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