Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
Department of Chemistry, Bates College, Lewiston, Maine 04240.
J Neurosci. 2021 Jan 27;41(4):578-593. doi: 10.1523/JNEUROSCI.1821-20.2020. Epub 2020 Dec 1.
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 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript ( ) encoding an N-terminally truncated TET1 protein and a full-length ( ) transcript encoding canonical TET1 are co-expressed in the adult mouse brain. We show that is the predominantly expressed isoform and is highly enriched in neurons, whereas 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, repression enhances, while impairs, hippocampal-dependent memory in male mice. Together, our findings demonstrate that each isoform serves a distinct role in the mammalian brain. 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 , 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 isoform serves a distinct role in the CNS.
DNA 甲基化在有丝分裂后神经元中的动态调控对于记忆形成和其他适应性行为是必要的。Ten-eleven translocation 1（TET1）通过将 5-甲基胞嘧啶（5mC）氧化为 5-羟甲基胞嘧啶（5hmC），从而启动活性 DNA 去甲基化，在这些过程中发挥作用。然而，由于最近的一项发现，即该基因的两个同工型从早期发育到成年期都有差异表达，因此试图确定其在神经系统中的确切作用一直受到矛盾结果的阻碍。在这里，我们证明了较短的转录本（）编码截短的 TET1 蛋白的 N 端，以及全长的（）转录本编码规范的 TET1 在成年小鼠大脑中都有表达。我们表明是主要表达的同工型，在神经元中高度富集，而则通常以较低的水平表达，在神经胶质细胞中更丰富，表明它们的作用至少部分是细胞类型特异性的。使用病毒介导的、同工型和神经元特异性分子工具，我们发现每个转录本的单独抑制导致独特的基因组合的失调和基础突触传递的相反变化。此外，在雄性小鼠中，的抑制增强了，而的抑制则损害了海马依赖记忆。总之，我们的研究结果表明，每个 同工型在哺乳动物大脑中都有独特的作用。在大脑中，基因表达的活性依赖性变化是形成长期记忆所必需的。DNA 甲基化在协调这些学习诱导的转录程序中起着至关重要的作用，通过影响染色质可及性和转录因子结合。曾经被认为是一种稳定的表观遗传标记，DNA 甲基化现在被认为是不稳定的和动态调节的，它在大脑的神经可塑性中起作用。我们发现，Ten-eleven translocation（TET）家族的酶成员之一，介导 DNA 甲基化标记的去除，在成年小鼠大脑中表达为两个独立的同工型，并且每个同工型都以不同的方式调节基因表达、突触传递和记忆形成。总之，我们的研究结果表明，每个 同工型在中枢神经系统中都有独特的作用。
