Departments of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
J Neurosci. 2012 Feb 1;32(5):1577-88. doi: 10.1523/JNEUROSCI.5180-11.2012.
Prolonged seizures (status epilepticus) produce pathophysiological changes in the hippocampus that are associated with large-scale, wide-ranging changes in gene expression. Epileptic tolerance is an endogenous program of cell protection that can be activated in the brain by previous exposure to a non-harmful seizure episode before status epilepticus. A major transcriptional feature of tolerance is gene downregulation. Here, through methylation analysis of 34,143 discrete loci representing all annotated CpG islands and promoter regions in the mouse genome, we report the genome-wide DNA methylation changes in the hippocampus after status epilepticus and epileptic tolerance in adult mice. A total of 321 genes showed altered DNA methylation after status epilepticus alone or status epilepticus that followed seizure preconditioning, with >90% of the promoters of these genes undergoing hypomethylation. These profiles included genes not previously associated with epilepsy, such as the polycomb gene Phc2. Differential methylation events generally occurred throughout the genome without bias for a particular chromosomal region, with the exception of a small region of chromosome 4, which was significantly overrepresented with genes hypomethylated after status epilepticus. Surprisingly, only few genes displayed differential hypermethylation in epileptic tolerance. Nevertheless, gene ontology analysis emphasized the majority of differential methylation events between the groups occurred in genes associated with nuclear functions, such as DNA binding and transcriptional regulation. The present study reports select, genome-wide DNA methylation changes after status epilepticus and in epileptic tolerance, which may contribute to regulating the gene expression environment of the seizure-damaged hippocampus.
长时间的癫痫发作（癫痫持续状态）会导致海马体产生病理生理变化，这些变化与基因表达的大规模、广泛变化有关。癫痫耐受是一种内源性的细胞保护程序，在癫痫持续状态之前，大脑可以通过先前暴露于无害的癫痫发作而被激活。耐受的一个主要转录特征是基因下调。在这里，通过对 34143 个离散的基因座进行甲基化分析，这些基因座代表了小鼠基因组中所有注释的 CpG 岛和启动子区域，我们报告了癫痫持续状态后和成年小鼠癫痫耐受时海马体的全基因组 DNA 甲基化变化。共有 321 个基因在癫痫持续状态后或癫痫持续状态后癫痫预处理后表现出 DNA 甲基化改变，这些基因的启动子中有超过 90%发生了低甲基化。这些图谱包括以前与癫痫无关的基因，如多梳基因 Phc2。差异甲基化事件通常发生在整个基因组中，没有特定染色体区域的偏向，除了染色体 4 的一小段区域，该区域在癫痫持续状态后发生低甲基化的基因显著富集。令人惊讶的是，只有少数基因在癫痫耐受中表现出差异超甲基化。然而，基因本体分析强调了两组之间的大多数差异甲基化事件发生在与核功能相关的基因中，如 DNA 结合和转录调控。本研究报告了癫痫持续状态后和癫痫耐受时的全基因组 DNA 甲基化变化，这些变化可能有助于调节癫痫损伤海马体的基因表达环境。
