Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia
Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia
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DOI：
10.1073/pnas.0505394102
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发表时间：
2005-08-30
影响因子：
11.1
通讯作者：
Guidotti, A
中科院分区：
文献类型：
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作者：
Dong, E;Agis-Balboa, RC;Guidotti, A
前额叶皮层谷氨酸脱羧酶（GAD（67））和reelin（mRNA和蛋白质）表达的减少是几项死后精神分裂症（SZ）大脑研究报告的最一致的发现。越来越多的证据表明，SZ大脑皮层GABA能中间神经元中GAD 67和reelin表达的减少是由于皮层GABA能中间神经元中DNA甲基转移酶1的过度表达介导的JNN和GAD 67启动子的表观遗传超甲基化。导致SZ脑中reelin和GAD 67下调的分子机制（DNA甲基化加上相关染色质重塑因子）的研究不仅对了解疾病发病机制而且对改善目前治疗SZ的药物干预具有重要意义。用L-甲硫氨酸处理的小鼠模拟了SZ中检测到的一些分子神经病理学，包括JNK启动子CpG岛的超甲基化以及reelin和GAD 67表达的下调。我们现在报告，在这些小鼠中，cDNAN和GAD 67启动子表达甲基CpG结合结构域蛋白的增加募集。在这些小鼠中，组蛋白去乙酰化酶抑制剂丙戊酸盐可增加皮质GABA能中间神经元中乙酰化组蛋白的含量，也可防止MET诱导的JNN启动子超甲基化，并减少甲基-CpG结合结构域蛋白与JNN和GAD 67启动子的结合。这些发现表明，DNA甲基化和相关的染色质重塑可能是至关重要的介导的reelin和GAD 67表达的表观遗传下调检测皮质GABA能中间神经元SZ患者。
Reduction of prefrontal cortex glutamic acid decarboxylase (GAD(67)) and reelin (mRNAs and proteins) expression is the most consistent finding reported by several studies of postmortem schizophrenia (SZ) brains. Converging evidence suggests that the reduced GAD67 and reelin expression in cortical GABAergic interneurons of SZ brains is the consequence of an epigenetic hypermethylation of RELN and GAD67 promoters very likely mediated by the overexpression of DNA methyltransferase 1 in cortical GABAergic interneurons. Studies of the molecular mechanisms (DNA methylation plus related chromatin remodeling factors) that cause the down-regulation of reelin and GAD67 in SZ brains have important implications not only to understand the disease pathogenesis but also to improve present pharmacological interventions to treat SZ. The mouse treated with L-methionine models some of the molecular neuropathologies detected in SZ, including the hypermethylation of RELN promoter CpG islands and the down-regulation of reelin and GAD67 expression. We now report that in these mice, RELN and GAD67 promoters express an increased recruitment of methyl-CpG binding domain proteins. In these mice the histone deacetylase inhibitor valproate, which increases acetylated histone content in cortical GABAergic interneurons, also prevents MET-induced RELN promoter hypermethylation and reduces the methyl-CpG binding domain protein binding to RELN and GAD67 promoters. These findings suggest that DNA hypermethylation and the associated chromatin remodeling may be critically important in mediating the epigenetic down-regulation of reelin and GAD67 expression detected in cortical GABAergic interneurons of SZ patients.