Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy
Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy
复制标题
DOI：
10.1016/j.ygeno.2019.09.020
复制
发表时间：
2020-03-01
期刊：
影响因子：
4.4
通讯作者：
Wang, Yonghua
中科院分区：
文献类型：
--
作者：
Fu, Yingxue;Wu, Ziyin;Wang, Yonghua
颞叶癫痫 (TLE) 是最常见且最具破坏性的癫痫形式。 TLE 发生的分子机制仍不清楚，这阻碍了有效抗癫痫药物的发现。在这里，我们采用了系统级方法，整合了三个癫痫发生阶段的转录组学特征，以确定癫痫进展的关键调节因子。将阶段特异性基因元特征与脑细胞特异性模块联系起来，揭示了癫痫发生过程中胶质细胞迁移和粘附、细胞因子产生和神经元死亡的正向调节，以及突触传递和离子转运的下调。我们确定了驱动这些过程的 265 个关键调节因子，其中 72 个被证明与人类 TLE 中的癫痫发作频率和/或海马硬化有关。重要的是，主要参与神经系统发育的 FAM107A、LAMB2、LTBP1 和 TGIF1 的上调被发现会导致这两种情况。我们的研究结果展示了癫痫发生的进化格局，并提供了可作为潜在抗癫痫发生靶点的候选调节因子。
Temporal lobe epilepsy (TLE) is the most prevalent and often devastating form of epilepsy. The molecular mechanism underlying the development of TLE remains largely unclear, which hinders the discovery of effective antiepileptogenic drugs. Here we adopted a systems-level approach integrating transcriptomic profiles of three epileptogenesis stages to identify key regulators underlying epilepsy progression. Associating stage-specific gene meta-signatures with brain cell-specialized modules revealed positive regulation of glial migration and adhesion, cytokine production, and neuron death, and downregulation of synaptic transmission and ion transport during epileptogenesis. We identified 265 key regulators driving these processes and 72 of them were demonstrated associating with seizure frequency and/or hippocampal sclerosis in human TLE. Importantly, the upregulation of FAM107A, LAMB2, LTBP1 and TGIF1, which are mainly involved in nervous system development, were found contributing to both conditions. Our findings present the evolution landscape of epileptogenesis and provide candidate regulators that may serve as potential antiepileptogenic targets.