Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
J Neurosci. 2010 May 26;30(21):7152-67. doi: 10.1523/JNEUROSCI.1314-10.2010.
Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair, and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to <1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30 kb downstream of the transcription start site. In hippocampus and ventral striatum, two key structures in the neuronal circuitry regulating mood-related behaviors, Setdb1-mediated repressive histone methylation at NR2B/Grin2b was associated with decreased NR2B expression and EPSP insensitivity to pharmacological blockade of NR2B, and accelerated NMDA receptor desensitization consistent with a shift in NR2A/B subunit ratios. In wild-type mice, systemic treatment with the NR2B antagonist, Ro25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol], and hippocampal small interfering RNA-mediated NR2B/Grin2b knockdown resulted in behavioral changes similar to those elicited by the Setdb1 transgene. Together, these findings point to a role for neuronal Setdb1 in the regulation of affective and motivational behaviors through repressive chromatin remodeling at a select set of target genes, resulting in altered NMDA receptor subunit composition and other molecular adaptations.
组蛋白 H3-赖氨酸 9 特异性的组蛋白甲基转移酶，包括 Setdb1（SET 域，分叉 1）/Eset/Kmt1e，与抑制性染色质重塑有关，并在成年大脑中表达，但它们对神经元功能和行为的潜在影响仍未被探索。在这里，我们报告说，在成年前脑神经元中表达增加的 Setdb1 的转基因小鼠在快感缺乏、绝望和习得性无助的行为范式中表现出抗抑郁样表型。结合 DNA 平铺阵列（ChIP-chip）的染色质免疫沉淀显示，神经元 Setdb1 的基因组占有率限制在<1%的注释基因，其中包括 NMDA 受体亚基 NR2B/Grin2B 和其他离子型谷氨酸受体基因。染色质构象捕获和 Setdb1-ChIP 显示了一种形成环的结构，将 NR2B/Grin2b 启动子固定在位于转录起始位点下游 30 kb 处的 Setdb1 靶位点上。在海马体和腹侧纹状体中，这两个调节与情绪相关行为的神经元回路的关键结构，Setdb1 介导的 NR2B/Grin2b 抑制性组蛋白甲基化与 NR2B 表达减少和 EPSP 对 NR2B 药理学阻断的不敏感有关，并加速 NMDA 受体脱敏，与 NR2A/B 亚基比率的变化一致。在野生型小鼠中，全身给予 NR2B 拮抗剂 Ro25-6981[R-（R，S）-α-（4-羟基苯基）-β-甲基-4-（苯甲基）-1-哌啶丙醇]和海马体小干扰 RNA 介导的 NR2B/Grin2b 敲低导致行为变化类似于 Setdb1 转基因引起的变化。总之，这些发现表明神经元 Setdb1 通过在一组选定的靶基因上进行抑制性染色质重塑，在调节情感和动机行为方面发挥作用，导致 NMDA 受体亚基组成和其他分子适应的改变。
