Setdb1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit NR2B.
Setdb1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit NR2B.
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DOI：
10.1523/jneurosci.1314-10.2010
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发表时间：
2010-05-26
期刊：
影响因子：
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通讯作者：
Akbarian S
中科院分区：
文献类型：
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作者：
Jiang Y;Jakovcevski M;Bharadwaj R;Connor C;Schroeder FA;Lin CL;Straubhaar J;Martin G;Akbarian S
组蛋白H3-赖氨酸9（H3 K9）残基特异性组蛋白甲基转移酶，包括Setdb 1（Set域，分叉1）/Eset/Kmt 1 e与抑制性染色质重塑相关，并在成人脑中表达，但对神经元功能和行为的潜在影响尚未探索。在这里，我们报告说，在成年前脑神经元Setdb 1表达增加的转基因小鼠表现出抗抑郁症样的表型在行为范式为快感缺乏，绝望和习得性无助。染色质免疫沉淀结合DNA拼接芯片（ChIP-chip）显示，神经元Setdb 1的基因组占有率仅限于不到1%的注释基因，其中包括NMDA受体亚基NR 2B/Grin 2B和其他离子型谷氨酸受体基因。染色质构象捕获（“3C”）和Setdb 1-ChIP揭示了将NR 2B/Grin 2b启动子拴系到位于转录起始位点下游30 Kb处的Setdb 1靶位点的环形成。在海马和腹侧纹状体（调节情绪相关行为的神经元回路中的两个关键结构）中，Setdb 1介导的NR 2 B/Grin 2 B b抑制性组蛋白甲基化与NR 2 B表达降低和EPSP对NR 2 B的药物阻断不敏感性相关，并加速NMDA受体脱敏，与NR 2 A/B亚基比例的变化一致。在野生型小鼠中，用NR 2B拮抗剂Ro-256981和海马siRNA介导的NR 2B/Grin 2b敲低进行全身治疗，导致与Setdb 1转基因引起的行为变化相似的行为变化。总之，这些发现指出神经元Setdb 1在调节情感和动机行为中的作用，通过在一组选定的靶基因上抑制染色质重塑，导致NMDA受体亚基组成和其他分子适应的改变。
Histone methyltransferases specific for the histone H3-lysine 9 (H3K9) 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 less than 1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture (“3C”) and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30Kb 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 wildtype mice, systemic treatment with the NR2B antagonist, Ro-256981, and hippocampal siRNA-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.