Epigenetic mechanisms are critical for hippocampus-dependent memory formation. Building on previous studies that implicate the N-lysine methyltransferase SETD6 in the activation of nuclear factor-κB RELA (also known as transcription factor p65) as an epigenetic recruiter, we hypothesized that SETD6 is a key player in the epigenetic control of long-term memory. Using a series of molecular, biochemical, imaging, electrophysiological, and behavioral experiments, we interrogated the effects of short interfering RNA–mediated knockdown of in the rat dorsal hippocampus during memory consolidation. Our findings demonstrate that SETD6 is necessary for memory-related nuclear factor-κB RELA methylation at lysine 310 and associated increases in H3K9me2 (histone H3 lysine 9 dimethylation) in the dorsal hippocampus and that SETD6 knockdown interferes with memory consolidation, alters gene expression patterns, and disrupts spine morphology. Together, these findings suggest that SETD6 plays a critical role in memory formation and may act as an upstream initiator of H3K9me2 changes in the hippocampus during memory consolidation.

中文翻译：

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SETD6 甲基转移酶在海马依赖性记忆形成中发挥重要作用


表观遗传机制对于海马依赖性记忆形成至关重要。之前的研究表明 N-赖氨酸甲基转移酶 SETD6 作为表观遗传募集剂参与核因子-κB RELA（也称为转录因子 p65）的激活，我们假设 SETD6 是长期表观遗传控制的关键参与者。记忆。通过一系列分子、生化、成像、电生理学和行为实验，我们探讨了记忆巩固过程中大鼠背侧海马体中短干扰 RNA 介导的敲低的效果。我们的研究结果表明，SETD6 对于记忆相关核因子-κB RELA 在赖氨酸 310 处的甲基化以及背侧海马中 H3K9me2（组蛋白 H3 赖氨酸 9 二甲基化）的相关增加是必需的，并且 SETD6 敲低会干扰记忆巩固，改变基因表达模式，并破坏脊柱形态。总之，这些发现表明 SETD6 在记忆形成中发挥着关键作用，并且可能在记忆巩固过程中充当海马 H3K9me2 变化的上游启动子。