Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA.
Cell Rep. 2022 Nov 8;41(6):111612. doi: 10.1016/j.celrep.2022.111612.
DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Viral-mediated neuronal overexpression and RNA interference of Tet2 altered dendritic complexity and synaptic-plasticity-related gene expression in vitro. Overexpression of neuronal Tet2 in adult hippocampus, and loss of Tet2 in adult glutamatergic neurons, resulted in differential hydroxymethylation associated with genes involved in synaptic transmission. Functionally, overexpression of neuronal Tet2 impaired hippocampal-dependent memory, while loss of neuronal Tet2 enhanced memory. Ultimately, these data identify neuronal Tet2 as a molecular target to boost cognitive function.
DNA 甲基化已成为神经元可塑性和认知功能的关键调节因子。尽管如此，去甲基化 DNA 的酶的作用仍有待充分探索。在这里，我们报告说，在成年神经元中丧失十号染色体缺失的转录因子 2（Tet2）会增强认知功能，Tet2 可催化 5-甲基胞嘧啶（5mC）氧化为 5-羟甲基胞嘧啶（5hmC）。在成年小鼠海马体中，我们检测到 Tet2 在神经元中的富集。病毒介导的神经元过表达和 Tet2 的 RNA 干扰改变了体外树突复杂性和与突触可塑性相关的基因表达。成年海马体中神经元 Tet2 的过表达和成年谷氨酸能神经元中 Tet2 的缺失导致与突触传递相关的基因的差异羟甲基化。功能上，神经元 Tet2 的过表达损害了海马体依赖性记忆，而神经元 Tet2 的缺失增强了记忆。最终，这些数据确定神经元 Tet2 是提高认知功能的分子靶标。
