Temporal lobe epilepsy is the most common and refractory form of epilepsy in adults. Gene expression within affected structures such as the hippocampus displays extensive dysregulation and is implicated as a central pathomechanism. Post-transcriptional mechanisms are increasingly recognized as determinants of the gene expression landscape, but key mechanisms remain unexplored. Here we show, for first time, that cytoplasmic mRNA polyadenylation, one of the post-transcriptional mechanisms regulating gene expression, undergoes widespread reorganization in temporal lobe epilepsy. In the hippocampus of mice subjected to status epilepticus and epilepsy, we report >25% of the transcriptome displays changes in their poly(A) tail length, with deadenylation disproportionately affecting genes previously associated with epilepsy. Suggesting cytoplasmic polyadenylation element binding proteins (CPEBs) being one of the main contributors to mRNA polyadenylation changes, transcripts targeted by CPEBs were particularly enriched among the gene pool undergoing poly(A) tail alterations during epilepsy. Transcripts bound by CPEB4 were over-represented among transcripts with poly(A) tail alterations and epilepsy-related genes and CPEB4 expression was found to be increased in mouse models of seizures and resected hippocampi from patients with drug-refractory temporal lobe epilepsy. Finally, supporting an adaptive function for CPEB4, deletion of Cpeb4 exacerbated seizure severity and neurodegeneration during status epilepticus and the development of epilepsy in mice. Together, these findings reveal an additional layer of gene expression regulation during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.

中文翻译：

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mRNA的聚腺苷酸化是颞叶癫痫中基因表达的新型调控机制。

颞叶癫痫是成人癫痫的最常见和难治性形式。受影响的结构（例如海马）中的基因表达显示出广泛的失调，并被认为是一种中央致病机制。转录后机制越来越被认为是基因表达格局的决定因素，但关键机制仍待探索。在这里，我们首次表明，胞质mRNA聚腺苷酸化是调节基因表达的转录后机制之一，在颞叶癫痫中发生了广泛的重组。在遭受癫痫持续状态和癫痫状态的小鼠海马中，我们报道了> 25％的转录组显示其poly（A）尾巴长度发生变化，其中腺苷酸化不成比例地影响了先前与癫痫相关的基因。提示胞质聚腺苷酸化元素结合蛋白（CPEB）是导致mRNA聚腺苷酸化变化的主要因素之一，CPEBs靶向的转录物在癫痫过程中经历了poly（A）尾部改变的基因库中尤其丰富。与CPEB4结合的转录本在带有poly（A）尾部改变和癫痫相关基因的转录本中被过度代表，并且在患有药物难治性颞叶癫痫的癫痫发作和切除海马模型中发现CPEB4表达增加。最后，支持CPEB4的自适应功能，删除 与CPEB4结合的转录本在带有poly（A）尾部改变和癫痫相关基因的转录本中被过度代表，并且在患有药物难治性颞叶癫痫的癫痫发作和切除海马模型中发现CPEB4表达增加。最后，支持CPEB4的自适应功能，删除 与CPEB4结合的转录本在带有poly（A）尾部改变和癫痫相关基因的转录本中被过度代表，并且在患有药物难治性颞叶癫痫的癫痫发作和切除海马模型中发现CPEB4表达增加。最后，支持CPEB4的自适应功能，删除Cpeb4在癫痫持续状态和小鼠癫痫发展过程中加剧了癫痫发作的严重性和神经变性。总之，这些发现揭示了癫痫发作期间基因表达调节的另一层，并指出了癫痫发作控制和疾病改变的新靶标。