Tet1 Isoforms Differentially Regulate Gene Expression, Synaptic Transmission, and Memory in the Mammalian Brain.
Tet1 Isoforms Differentially Regulate Gene Expression, Synaptic Transmission, and Memory in the Mammalian Brain.
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DOI：
10.1523/jneurosci.1821-20.2020
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发表时间：
2021-01-27
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影响因子：
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通讯作者：
Kaas GA
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文献类型：
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作者：
Greer CB;Wright J;Weiss JD;Lazarenko RM;Moran SP;Zhu J;Chronister KS;Jin AY;Kennedy AJ;Sweatt JD;Kaas GA
有丝分裂后神经元DNA甲基化的动态调节是记忆形成和其他适应性行为所必需的。TET 1通过将5-甲基胞嘧啶（5 mC）氧化为5-羟甲基胞嘧啶（5 hmC），从而启动活性DNA去甲基化，在这些过程中发挥作用。然而，试图确定其在神经系统中的确切作用受到了矛盾的发现的阻碍，这可能部分是由于最近发现Tet 1基因的两种亚型从早期发育到成年期的差异表达。在这里，我们证明了两个较短的转录（Tet 1 S）编码的N-末端截短的TET 1蛋白和全长Tet 1（Tet 1FL）转录编码典型的TET 1在成年小鼠大脑中共表达。我们发现，Tet 1 S是主要表达的亚型，是高度富集的神经元，而Tet 1FL通常在较低的水平和更丰富的神经胶质细胞表达，这表明它们的作用至少部分细胞类型特异性。使用病毒介导的，同种型和神经元特异性的分子工具，我们发现，每个转录本的个体抑制导致独特的基因集合失调和基础突触传递的对比变化。此外，Tet 1 S抑制增强，而Tet 1FL损害，在雄性小鼠中的海马依赖性记忆。总之，我们的研究结果表明，每个Tet 1亚型在哺乳动物大脑中起着不同的作用。意义陈述在大脑中，长期记忆的形成需要基因表达的活动依赖性变化。DNA甲基化通过影响染色质可及性和转录因子结合，在协调这些学习诱导的转录程序中发挥着重要作用。DNA甲基化曾经被认为是一种稳定的表观遗传标记，现在已知它是非永久性的和动态调节的，驱动大脑中的神经可塑性。我们发现Tet 1是介导DNA甲基标记去除的10 - 11易位（泰特）酶家族的一员，在成年小鼠脑中表达为两种不同的同种型，每种同种型均差异调节基因表达、突触传递和记忆形成。总之，我们的研究结果表明，每个Tet 1亚型在中枢神经系统中起着不同的作用。
The dynamic regulation of DNA methylation in postmitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the Tet1 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (Tet1S) encoding an N-terminally truncated TET1 protein and a full-length Tet1 (Tet1FL) transcript encoding canonical TET1 are co-expressed in the adult mouse brain. We show that Tet1S is the predominantly expressed isoform and is highly enriched in neurons, whereas Tet1FL is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell type-specific. Using viral-mediated, isoform and neuron-specific molecular tools, we find that the individual repression of each transcript leads to the dysregulation of unique gene ensembles and contrasting changes in basal synaptic transmission. In addition, Tet1S repression enhances, while Tet1FL impairs, hippocampal-dependent memory in male mice. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the mammalian brain. SIGNIFICANCE STATEMENT In the brain, activity-dependent changes in gene expression are required for the formation of long-term memories. DNA methylation plays an essential role in orchestrating these learning-induced transcriptional programs by influencing chromatin accessibility and transcription factor binding. Once thought of as a stable epigenetic mark, DNA methylation is now known to be impermanent and dynamically regulated, driving neuroplasticity in the brain. We found that Tet1, a member of the ten-eleven translocation (TET) family of enzymes that mediates removal of DNA methyl marks, is expressed as two separate isoforms in the adult mouse brain and that each differentially regulates gene expression, synaptic transmission and memory formation. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the CNS.