Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, Alabama.
Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, Alabama.
Biol Psychiatry. 2020 Mar 15;87(6):577-587. doi: 10.1016/j.biopsych.2019.05.022. Epub 2019 Jun 12.
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 Setd6 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.
表观遗传机制对于海马体依赖的记忆形成至关重要。基于先前的研究表明，N-赖氨酸甲基转移酶 SETD6 作为一种表观遗传招募因子，激活核因子-κB RELA（也称为转录因子 p65），我们假设 SETD6 是长时记忆的表观遗传控制的关键因素。
使用一系列分子、生化、成像、电生理和行为实验，我们在记忆巩固期间探究了短干扰 RNA 介导的 SETD6 在大鼠背侧海马体中的敲低对记忆相关核因子-κB RELA 赖氨酸 310 甲基化和相关的 H3K9me2（组蛋白 H3 赖氨酸 9 二甲基化）增加的影响。
我们的发现表明，SETD6 是背侧海马体中记忆相关核因子-κB RELA 赖氨酸 310 甲基化和相关的 H3K9me2 增加所必需的，并且 SETD6 敲低会干扰记忆巩固、改变基因表达模式，并破坏棘突形态。
综上所述，这些发现表明 SETD6 在记忆形成中起着关键作用，并且可能作为记忆巩固期间海马体中 H3K9me2 变化的上游启动子。
