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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex
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Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex

机译:前额叶皮层神经元H3K4me3表观基因组的发育调控和个体差异

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摘要

Little is known about the regulation of neuronal and other cell-type specific epigenomes from the brain. Here, we map the genome-wide distribution of trimethylated histone H3K4 (H3K4me3), a mark associated with transcriptional regulation, in neuronal and non-neuronal nuclei collected from prefrontal cortex (PFC) of 11 individuals ranging in age from 0.5 to 69 years. Massively parallel sequencing identified 12,732-19,704 H3K4me3 enriched regions (peaks), the majority located proximal to (within 2 kb of) the transcription start site (TSS) of annotated genes. These included peaks shared by neurons in comparison with three control (lymphocyte) cell types, as well as peaks specific to individual subjects. We identified 6,213 genes that show highly enriched H3K4me3 in neurons versus control. At least 1,370 loci, including annotated genes and novel transcripts, were selectively tagged with H3K4me3 in neuronal but not in nonneuronal PFC chromatin. Our results reveal age-correlated neuronal epigenome reorganization, including decreased H3K4me3 at approximately 600 genes (many function in developmental processes) during the first year after birth. In comparison, the epigenome of aging (>60 years) PFC neurons showed less extensive changes, including increased H3K4me3 at 100 genes. These findings demonstrate that H3K4me3 in human PFC is highly regulated in a cell type- and subject-specific manner and highlight the importance of early childhood for developmentally regulated chromatin remodeling in prefrontal neurons.
机译:关于大脑神经元和其他细胞类型特异性表观基因组的调控知之甚少。在这里,我们绘制了三甲基化组蛋白H3K4(H3K4me3)(与转录调控相关的标记)在全基因组范围内的分布,该分布是从11个年龄在0.5至69岁的个体的前额叶皮层(PFC)收集的神经元和非神经元核中。大规模平行测序确定了12,732-19,704个H3K4me3富集区域(峰),大部分位于注释基因的转录起始位点(TSS)附近(2 kb之内)。这些包括与三种对照(淋巴细胞)细胞类型相比,神经元共有的峰,以及特定个体的峰。我们确定了6,213个基因,它们在神经元中相对于对照显示出高度丰富的H3K4me3。至少1,370个基因座,包括带注释的基因和新的转录本,在神经元中被选择性标记为H3K4me3,但在非神经元PFC染色质中未被标记。我们的研究结果揭示了年龄相关的神经元表观基因组重组,包括出生后第一年内约600个基因(发育过程中的许多功能)的H3K4me3减少。相比之下,衰老(> 60年)的PFC神经元的表观基因组显示出较少的广泛变化,包括100个基因处的H3K4me3增加。这些发现表明,人PFC中的H3K4me3以细胞类型和受试者特异性的方式受到高度调节,并突显了幼儿期对于额叶前额神经元发育中的染色质重塑的重要性。

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  • 作者单位

    Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604;

    Biomedical Engineering, Boston University, Boston MA 02215;

    Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604;

    Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604;

    Program in Bioinformatics and Integrative Biology,University of Massachusetts Medical School, Worcester, MA 01604;

    Biomedical Engineering, Boston University, Boston MA 02215 Program in Bioinformatics and Integrative Biology,University of Massachusetts Medical School, Worcester, MA 01604 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01604;

    Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cerebral cortex; neuron; histone methylation; human; brain; gene expression;

    机译:大脑皮层神经元组蛋白甲基化人脑;基因表达;

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