Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters
Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters
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DOI：
10.1523/jneurosci.3272-07.2007
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发表时间：
2007-10-17
影响因子：
5.3
通讯作者：
Akbarian, Schahram
中科院分区：
文献类型：
--
作者：
Huang, Hsien-Sung;Matevossian, Anouch;Akbarian, Schahram
GABAergic mRNA 表达的改变在精神分裂症和其他神经发育疾病的前额叶功能障碍中发挥着关键作用。在这里，我们发现，从产前到青春期前后以及整个成年期，人类前额皮质（PFC）中的 GAD1 和其他 GABA 能基因启动子（GAD2、NPY、SST）的组蛋白 H3-赖氨酸 4 甲基化（一种与转录过程相关的染色质标记）逐渐增加。精神分裂症的改变包括 GAD1 表达减少和 H3K4 三甲基化，主要发生在女性中，并与 GAD1 5' 端的风险单倍型相关。混合谱系白血病 1 (Mll1)（一种在 GABA 能和其他皮质神经元中表达的组蛋白甲基转移酶）的截短 lacZ 敲入等位基因的杂合性导致 GABA 能基因启动子处的 H3K4 甲基化减少。相比之下，在使用非典型抗精神病药物氯氮平治疗后，小鼠大脑皮层中的 Gad1 H3K4 (tri) 甲基化和 Mll1 占有率增加。氟哌啶醇或多巴胺 D-2 和 D-3 受体的基因消除无法模拟这些效应，这表明 D-2 样信号传导的阻断不足以抑制氯氮平诱导的组蛋白甲基化。因此，GABA能基因启动子的染色质重塑机制，包括MLL1介导的组蛋白甲基化，在正常人类PFC发育的较长时期内发挥作用，并在精神分裂症的神经生物学中发挥作用。
Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters (GAD2, NPY, SST) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5' end of GAD1. Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 ( Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, Gad1 H3K4 (tri) methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D-2 and D-3 receptors, suggesting that blockade of D-2-like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia.