Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nat Neurosci. 2011 Aug 28;14(10):1345-51. doi: 10.1038/nn.2900.
DNA methylation has been traditionally viewed as a highly stable epigenetic mark in postmitotic cells. However, postnatal brains appear to show stimulus-induced methylation changes, at least in a few identified CpG dinucleotides. How extensively the neuronal DNA methylome is regulated by neuronal activity is unknown. Using a next-generation sequencing-based method for genome-wide analysis at single-nucleotide resolution, we quantitatively compared the CpG methylation landscape of adult mouse dentate granule neurons in vivo before and after synchronous neuronal activation. About 1.4% of 219,991 CpGs measured showed rapid active demethylation or de novo methylation. Some modifications remained stable for at least 24 h. These activity-modified CpGs showed a broad genomic distribution with significant enrichment in low-CpG density regions, and were associated with brain-specific genes related to neuronal plasticity. Our study implicates modification of the neuronal DNA methylome as a previously underappreciated mechanism for activity-dependent epigenetic regulation in the adult nervous system.
DNA 甲基化传统上被认为是有丝分裂后细胞中一种高度稳定的表观遗传标记。然而，出生后的大脑似乎表现出刺激诱导的甲基化变化，至少在一些已确定的 CpG 二核苷酸中如此。神经元活性对神经元 DNA 甲基组的调控程度尚不清楚。我们使用基于下一代测序的全基因组单核苷酸分辨率分析方法，在同步神经元激活前后，定量比较了成年小鼠齿状回颗粒神经元体内的 CpG 甲基化景观。在测量的 219911 个 CpG 中，约有 1.4% 表现出快速的活性去甲基化或从头甲基化。一些修饰至少稳定 24 小时。这些活性修饰的 CpG 具有广泛的基因组分布，在低 CpG 密度区域有显著富集，并与与神经元可塑性相关的大脑特异性基因相关。我们的研究表明，神经元 DNA 甲基组的修饰是成年神经系统中活性依赖性表观遗传调控的一个以前未被充分认识的机制。
