Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus.
Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus.
复制标题
DOI：
10.1038/ncomms7031
复制
发表时间：
2015-01-23
影响因子：
16.6
通讯作者：
Petretto E
中科院分区：
文献类型：
--
作者：
Johnson MR;Behmoaras J;Bottolo L;Krishnan ML;Pernhorst K;Santoscoy PLM;Rossetti T;Speed D;Srivastava PK;Chadeau-Hyam M;Hajji N;Dabrowska A;Rotival M;Razzaghi B;Kovac S;Wanisch K;Grillo FW;Slaviero A;Langley SR;Shkura K;Roncon P;De T;Mattheisen M;Niehusmann P;O'Brien TJ;Petrovski S;von Lehe M;Hoffmann P;Eriksson J;Coffey AJ;Cichon S;Walker M;Simonato M;Danis B;Mazzuferi M;Foerch P;Schoch S;De Paola V;Kaminski RM;Cunliffe VT;Becker AJ;Petretto E
基因调控网络分析是阐明复杂疾病的分子过程和途径的有力方法。在这里，我们采用系统遗传学方法来表征人类颞叶癫痫（TLE）病理生理途径的遗传调控。利用129例TLE患者手术获得的海马体，我们发现了一个与癫痫遗传相关的基因调控网络，该网络包含一个专门的、高表达的转录模块，编码前惊厥细胞因子和toll样受体信号基因。对小鼠TLE模型的RNA测序分析显示，前惊痫模块跨物种保存，特异于癫痫海马，在慢性癫痫中上调。在TLE患者中，我们将这种前惊厥模块的反式基因控制定位于SESN3，并证明SESN3在巨噬细胞、小胶质细胞和神经元中正调控该模块。在斑马鱼中，morpholino介导的Sesn3敲低证实了转录模块的调节，并减轻了体内化学诱导的行为癫痫发作。
Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo.