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Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy

机译：系统级别分析识别颞叶癫痫患者癫痫发作的关键调节器

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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.
机译：颞叶癫痫（TLE）是最普遍，最常见的癫痫形式。底层发育的分子机制在很大程度上尚不清楚，阻碍了有效的抗癫痫药物的发现。在这里，我们采用了一种整合三个癫痫阶段转录组谱的系统级方法，以识别癫痫进展的关键调节因素。将特定阶段特异性基因间签名与脑细胞专用模块揭示了胶质迁移和粘附，细胞因子生产和神经元死亡的正规调控，并在癫痫发​​生期间下调突触传递和离子输送的下调。我们确定了驾驶这些方法的265个关键调节器，并证明它们的72种与人类TLE中的癫痫发作和/或海马硬化症相关联。重要的是，发现主要参与神经系统发育的FAM107A，LAMB2，LTBP1和TGIF1的上调促成了两种情况。我们的研究结果呈现了癫痫发生的进化景观，并提供了可作为潜在的抗癫痫症靶标的候选调节剂。

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