Bioinformatic analysis identifies key transcriptome signatures in temporal lobe epilepsy.
Bioinformatic analysis identifies key transcriptome signatures in temporal lobe epilepsy.
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生物信息分析确定颞叶癫痫的关键转录组特征
DOI：
10.1111/cns.13470
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发表时间：
2020-12
影响因子：
5.5
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Chen QL;Xia L;Zhong SP;Wang Q;Ding J;Wang X
识别颞叶癫痫（TLE）癫痫发生的转录组特征。稳健的秩聚合分析被用来整合多个微阵列在啮齿动物模型的TLE和确定差异表达的基因（DEG）在急性，潜伏期和慢性阶段。进行功能注释和蛋白质-蛋白质相互作用分析以探索DEG的潜在功能并鉴定具有最高模块内连接性的枢纽基因。使用来自TLE患者的公开可用的RNA测序数据集分析了中枢基因与海马硬化/癫痫发作频率之间的关联。随后，我们在大鼠中建立了匹鲁卡品诱导的癫痫持续状态（SE）模型，并通过定量逆转录PCR（qRT-PCR）验证了hub基因的mRNA表达。在动物模型中，TLE急性期、潜伏期和慢性期的DEG均明显富集于炎症反应。在急性期鉴定的Hub基因主要参与生物学过程，包括炎症、血脑屏障损伤和细胞粘附。潜伏期的中枢基因与小胶质细胞/巨噬细胞活化（Emr 1和Aif 1）和吞噬作用（Cd 68，Tyrobp和Lyz）有关。在慢性期，枢纽基因与补体和小胶质细胞/巨噬细胞的激活相关。我们进一步发现，在人类TLE中鉴定的一些枢纽基因，如Tlr 2，Lgals 3和Stat 3，与癫痫发作频率呈正相关。其他枢纽基因，包括Lgals 3和Serpine 1，与海马硬化有关。qRT-PCR分析证实，SE诱导后大鼠海马中hub基因的mRNA水平显著上调。我们的综合分析确定了癫痫不同阶段的枢纽基因。功能注释表明小胶质细胞/巨噬细胞的激活和吞噬活动可能在TLE的癫痫发生中发挥关键作用。激活的吞噬小胶质细胞可能调节颞叶癫痫（TLE）异常神经回路的形成。致癫痫损伤后，海马中的小胶质细胞被上调的溶酶体分子激活，包括CD 68、LAMP 1、LYZ和LAPTM 5。吞噬相关分子如C1 QA、C1 QB、C3和TYROBP的表达也上调。活化的吞噬小胶质细胞可在补体和TYROBP的作用下吞噬凋亡神经元、新生神经元和突触，从而调节TLE异常的神经回路和癫痫的发生。在慢性期，自发性癫痫发作的发生进一步激活了小胶质细胞和补体，加剧了异常的神经回路。
To identify transcriptome signatures underlying epileptogenesis in temporal lobe epilepsy (TLE). Robust rank aggregation analysis was used to integrate multiple microarrays in rodent models of TLE and determine differentially expressed genes (DEGs) in acute, latent, and chronic stages. Functional annotation and protein‐protein interaction analysis were performed to explore the potential functions of the DEGs and identify hub genes with the highest intramodular connectivity. The association between hub genes and hippocampal sclerosis/seizure frequency was analyzed using publicly available RNA‐sequencing datasets from TLE patients. We subsequently established a pilocarpine‐induced status epilepticus (SE) model in rats and validated mRNA expression of hub genes by quantitative reverse transcription PCR (qRT‐PCR). The DEGs in the acute, latent, and chronic phases of TLE in animal models were prominently enriched in inflammatory response. Hub genes identified in the acute phase mainly participated in biological processes including inflammation, blood‐brain barrier damage, and cell adhesion. The hub genes in the latent phase were related to microglia/macrophage activation (Emr1 and Aif1) and phagocytosis (Cd68, Tyrobp, and Lyz). In the chronic phase, the hub genes were associated with activation of complements and microglia/macrophages. We further found that some hub genes identified in human TLE, such as Tlr2, Lgals3, and Stat3, were positively correlated with seizure frequency. Other hub genes, including Lgals3 and Serpine1, were associated with hippocampus sclerosis. qRT‐PCR analysis confirmed that the mRNA levels of hub genes in rat hippocampus were significantly up‐regulated after SE induction. Our integrated analysis identified hub genes in different stages of epilepsy. The functional annotations suggest that the activation and phagocytic activities of microglia/macrophages may play critical roles in epileptogenesis of TLE. Activated phagocytic microglia may regulate the formation of abnormal neural circuits in temporal lobe epilepsy (TLE). After an epileptogenic injury, microglia in hippocampus was activated with up‐regulated lysosomal molecules including CD68, LAMP1, LYZ, and LAPTM5. The expressions of phagocytosis‐related molecules like C1QA, C1QB, C3, and TYROBP were also up‐regulated. Activated phagocytic microglia could engulf apoptosis neurons, newborn neurons, and synapse with the help of complement and TYROBP, thus regulating the abnormal neural circuits and epileptogenesis in TLE. In chronic stage, the occurrence of spontaneous seizures further activated microglia and complements and exacerbated abnormal neuronal circuits.
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影响因子：
5.6
作者：
CAVALHEIRO, EA;LEITE, JP;TURSKI, L
通讯作者：
TURSKI, L
影响因子：
4.4
作者：
Fu, Yingxue;Wu, Ziyin;Wang, Yonghua
通讯作者：
Wang, Yonghua
影响因子：
6.1
作者：
Grabenstatter HL;Del Angel YC;Carlsen J;Wempe MF;White AM;Cogswell M;Russek SJ;Brooks-Kayal AR
通讯作者：
Brooks-Kayal AR
影响因子：
6.3
作者：
Kurisu, Kota;Zheng, Zhen;Yenari, Midori A.
通讯作者：
Yenari, Midori A.
影响因子：
8.3
作者：
Denorme, Frederik;Wyseure, Tine;De Meyer, Simon F.
通讯作者：
De Meyer, Simon F.