The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states.
The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states.
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DOI：
10.1038/srep40127
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发表时间：
2017-01-05
影响因子：
4.6
通讯作者：
Wolvetang EJ
中科院分区：
文献类型：
--
作者：
Barry G;Briggs JA;Hwang DW;Nayler SP;Fortuna PR;Jonkhout N;Dachet F;Maag JL;Mestdagh P;Singh EM;Avesson L;Kaczorowski DC;Ozturk E;Jones NC;Vetter I;Arriola-Martinez L;Hu J;Franco GR;Warn VM;Gong A;Dinger ME;Rigo F;Lipovich L;Morris MJ;O'Brien TJ;Lee DS;Loeb JA;Blackshaw S;Mattick JS;Wolvetang EJ
尽管它们丰富，但哺乳动物神经系统中长非编码RNA的分子功能仍然知之甚少。在这里，我们表明，长的非编码RNA，NEAT 1，直接调节神经元的兴奋性，并与病理性癫痫发作状态。具体而言，NEAT 1在体外和体内受神经元活性动态调节，结合癫痫相关钾通道相互作用蛋白（包括KCNAB 2和KCNIP 1），并在反义寡核苷酸敲低后诱导iPSC衍生的人皮质神经元中的神经元超增强表型。下一代测序揭示了NEAT 1与在NEAT 1敲低后iPSC衍生的神经元激活后增加的离子通道基因表达的强关联。此外，我们表明，虽然NEAT 1是急性下调响应神经元的活动，重复刺激的结果NEAT 1成为慢性无反应的独立在体内大鼠模型系统相关的颞叶癫痫。我们扩展了先前的研究，显示在切除的皮质组织中NEAT 1表达增加，这些皮质组织来自患有难治性癫痫发作的患者的高尖峰区域。我们的研究结果表明NEAT 1在调节人类神经元活动中的作用，并表明活动依赖性长非编码RNA和癫痫之间存在一种新的机制联系。
Despite their abundance, the molecular functions of long non-coding RNAs in mammalian nervous systems remain poorly understood. Here we show that the long non-coding RNA, NEAT1, directly modulates neuronal excitability and is associated with pathological seizure states. Specifically, NEAT1 is dynamically regulated by neuronal activity in vitro and in vivo, binds epilepsy-associated potassium channel-interacting proteins including KCNAB2 and KCNIP1, and induces a neuronal hyper-potentiation phenotype in iPSC-derived human cortical neurons following antisense oligonucleotide knockdown. Next generation sequencing reveals a strong association of NEAT1 with increased ion channel gene expression upon activation of iPSC-derived neurons following NEAT1 knockdown. Furthermore, we show that while NEAT1 is acutely down-regulated in response to neuronal activity, repeated stimulation results in NEAT1 becoming chronically unresponsive in independent in vivo rat model systems relevant to temporal lobe epilepsy. We extended previous studies showing increased NEAT1 expression in resected cortical tissue from high spiking regions of patients suffering from intractable seizures. Our results indicate a role for NEAT1 in modulating human neuronal activity and suggest a novel mechanistic link between an activity-dependent long non-coding RNA and epilepsy.
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
11
作者：
Barry, G.;Briggs, J. A.;Mattick, J. S.
通讯作者：
Mattick, J. S.
影响因子：
12.3
作者：
Kim D;Pertea G;Trapnell C;Pimentel H;Kelley R;Salzberg SL
通讯作者：
Salzberg SL
DOI：
10.1083/jcb.201011110
发表时间：
2011-04-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nakagawa S;Naganuma T;Shioi G;Hirose T
通讯作者：
Hirose T
DOI：
10.1074/mcp.o111.016253
发表时间：
2012-06
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Jeong JS;Jiang L;Albino E;Marrero J;Rho HS;Hu J;Hu S;Vera C;Bayron-Poueymiroy D;Rivera-Pacheco ZA;Ramos L;Torres-Castro C;Qian J;Bonaventura J;Boeke JD;Yap WY;Pino I;Eichinger DJ;Zhu H;Blackshaw S
通讯作者：
Blackshaw S