title: The Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington's Disease.
abstract: 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.
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, United States of America.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Dong
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, United States of America.
authors.forename: Junko
authors.initials: J
authors.lastname: Tsuji
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.|Bioinformatics Program, Boston University, Boston, MA, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Labadorf
authors.affiliation: Friedman Brain Institute, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, United States of America.|Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, United States of America.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.|Bioinformatics Program, Boston University, Boston, MA, United States of America.|Genome Science Institute, Boston University School of Medicine, Boston, MA, United States of America.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.affiliation: Friedman Brain Institute, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, United States of America.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, United States of America.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
mesh_terms: D000328:Adult; D000368:Aged; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D005786:Gene Expression Regulation; D063990:Gene Ontology; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis / Q000235:genetics; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: C086055:HTT protein, human; D006657:Histones; D000071058:Huntingtin Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2