Activity-Dependent Non-Coding RNA MAPK Interactome of the Human Epileptic Brain.
Activity-Dependent Non-Coding RNA MAPK Interactome of the Human Epileptic Brain.
复制标题
DOI：
10.3390/ncrna9010003
复制
发表时间：
2023-01-04
期刊：
影响因子：
4.3
通讯作者：
Loeb JA
中科院分区：
文献类型：
--
作者：
Kirchner A;Dachet F;Lipovich L;Loeb JA
人类的大脑已经进化到具有非凡的能力，使复杂的行为成为可能。人类大脑的独特性越来越被认为在一定程度上是由于灵长类特有的功能，包括人类特有的长非编码RNA(LncRNA)基因，在进化过程中系统地低于蛋白质编码基因的保守性。对接受抗药性癫痫手术的患者进行广泛的脑组织电记录，然后将其移除以治疗他们的癫痫。具有不同电学性质的脑组织的精确定位为探索大脑活动对基因表达的影响提供了难得的机会。在这里，我们在人类MAPK信号级联中发现了231个共同调节的、活性依赖的lncRNA。进一步检测了6个lncRNAs，其中4个与已知的蛋白质编码基因反义，因为它们的高表达和对疾病表型的潜在影响。利用人类神经元样细胞重复去极化的模型(Sh-SY5Y)，我们发现六个lncRNA中有五个是电活动依赖的，四个反义lncRNA中有三个相对于它们的蛋白质编码基因伙伴具有相互表达的模式。一些基因受到MAPK信号的直接调控，而另一些基因则有效地下调了编码在其基因组座位相反链上的蛋白质编码基因的表达。因此，这些lncRNAs可能有助于高度进化和灵长类动物特有的人类大脑调节功能，这些功能可以通过治疗调节来治疗癫痫。
The human brain has evolved to have extraordinary capabilities, enabling complex behaviors. The uniqueness of the human brain is increasingly posited to be due in part to the functions of primate-specific, including human-specific, long non-coding RNA (lncRNA) genes, systemically less conserved than protein-coding genes in evolution. Patients who have surgery for drug-resistant epilepsy are subjected to extensive electrical recordings of the brain tissue that is subsequently removed in order to treat their epilepsy. Precise localization of brain tissues with distinct electrical properties offers a rare opportunity to explore the effects of brain activity on gene expression. Here, we identified 231 co-regulated, activity-dependent lncRNAs within the human MAPK signaling cascade. Six lncRNAs, four of which were antisense to known protein-coding genes, were further examined because of their high expression and potential impact on the disease phenotype. Using a model of repeated depolarizations in human neuronal-like cells (Sh-SY5Y), we show that five out of six lncRNAs were electrical activity-dependent, with three of four antisense lncRNAs having reciprocal expression patterns relative to their protein-coding gene partners. Some were directly regulated by MAPK signaling, while others effectively downregulated the expression of the protein-coding genes encoded on the opposite strands of their genomic loci. These lncRNAs, therefore, likely contribute to highly evolved and primate-specific human brain regulatory functions that could be therapeutically modulated to treat epilepsy.