Histone methylation at H3K9: evidence for a restrictive epigenome in schizophrenia.
Histone methylation at H3K9: evidence for a restrictive epigenome in schizophrenia.
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DOI：
10.1016/j.schres.2013.06.021
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发表时间：
2013-09
影响因子：
4.5
通讯作者：
Sharma RP
中科院分区：
文献类型：
--
作者：
Chase KA;Gavin DP;Guidotti A;Sharma RP
表观遗传变化是稳定且持久的染色质修饰，可调节全基因组和局部基因活性。组蛋白甲基转移酶 (HMT) 在组蛋白 3 (H3K9me2) 的第 9 个赖氨酸上添加两个甲基，导致限制性染色质状态，从而降低基因转录水平。鉴于精神分裂症候选基因转录下调的大量报道，我们检验了这种疾病可以以限制性表观基因组为特征的假设。我们从斯坦利基金会神经病理学联盟获得了顶叶皮质样本，从伊利诺伊大学芝加哥分校 (UIC) 获得了淋巴细胞样本。在这两种组织中，我们通过实时 RT-PCR 测量了 HMT GLP、SETDB1 和 G9a 的 mRNA 表达，并通过蛋白质印迹测量了 H3K9me2 水平。临床评定量表是从 UIC 队列中获得的。精神分裂症的诊断是死后大脑和淋巴细胞样本中 GLP、SETDB1 mRNA 表达和 H3K9me2 水平增加的重要预测因子。 UIC 淋巴细胞样本中的 G9a mRNA 也显着增加。 HMT mRNA 表达增加与特定症状恶化、病程延长和精神分裂症家族史相关。这些数据支持精神分裂症中限制性表观基因组的假设，并且可能与众所周知的治疗耐药性症状相关。这里测量的组蛋白甲基转移酶是小分子药理学未来潜在的治疗靶点，可以改善患者的预后。
Epigenetic changes are stable and long-lasting chromatin modifications that regulate genomewide and local gene activity. The addition of two methyl groups to the 9th lysine of histone 3 (H3K9me2) by histone methyltransferases (HMT) leads to a restrictive chromatin state, and thus reduced levels of gene transcription. Given the numerous reports of transcriptional down-regulation of candidate genes in schizophrenia, we tested the hypothesis that this illness can be characterized by a restrictive epigenome. We obtained parietal cortical samples from the Stanley Foundation Neuropathology Consortium and lymphocyte samples from the University of Illinois at Chicago (UIC). In both tissues we measured mRNA expression of HMTs GLP, SETDB1 and G9a via real-time RT-PCR and H3K9me2 levels via western blot. Clinical rating scales were obtained from the UIC cohort. A diagnosis of schizophrenia is a significant predictor for increased GLP, SETDB1 mRNA expression and H3K9me2 levels in both postmortem brain and lymphocyte samples. G9a mRNA is significantly increased in the UIC lymphocyte samples as well. Increased HMT mRNA expression is associated with worsening of specific symptoms, longer durations of illness and a family history of schizophrenia. These data support the hypothesis of a restrictive epigenome in schizophrenia, and may associate with symptoms that are notoriously treatment resistant. The histone methyltransferases measured here are potential future therapeutic targets for small molecule pharmacology, and better patient prognosis.
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