Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex
Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex
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DOI：
10.1073/pnas.1001702107
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发表时间：
2010-05-11
影响因子：
11.1
通讯作者：
Akbarian, Schahram
中科院分区：
文献类型：
--
作者：
Cheung, Iris;Shulha, Hennady P.;Akbarian, Schahram
关于来自大脑的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，我们绘制了全基因组分布的三甲基化组蛋白H3 K4（H3 K4 me 3），一个标记与转录调控，在神经元和非神经元的核收集从前额叶皮层（PFC）的11个人的年龄范围从0.5至69岁。大规模平行测序鉴定了12，732 - 19，704个H3 K4 me 3富集区（峰），大多数位于注释基因的转录起始位点（TSS）附近（在2kb内）。这些包括与三种对照（淋巴细胞）细胞类型相比由神经元共享的峰，以及个体受试者特有的峰。我们鉴定了6，213个基因，这些基因在神经元中与对照组相比显示出高度富集的H3 K4 me 3。至少有1,370个位点，包括注释的基因和新的转录本，选择性标记H3 K4 me 3在神经元，但不是在非神经元PFC染色质。我们的结果揭示了与年龄相关的神经元表观基因组重组，包括出生后第一年内大约600个基因（许多在发育过程中发挥作用）的H3 K4 me 3减少。相比之下，老化（> 60岁）PFC神经元的表观基因组显示出不太广泛的变化，包括100个基因的H3 K4 me 3增加。这些研究结果表明，H3 K4 me 3在人类PFC是高度调节的细胞类型和受试者特异性的方式，并强调了儿童早期发育调节的染色质重塑在前额叶神经元的重要性。
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 nonneuronal 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.