Evidence of a sex-dependent restrictive epigenome in schizophrenia.
Evidence of a sex-dependent restrictive epigenome in schizophrenia.
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DOI：
10.1016/j.jpsychires.2015.04.005
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发表时间：
2015-06
影响因子：
4.8
通讯作者：
Sharma, Rajiv P.
中科院分区：
文献类型：
--
作者：
Chase, Kayla A.;Rosen, Cherise;Rubin, Leah H.;Feiner, Benjamin;Bodapati, Anjuli S.;Gin, Hannah;Hu, Edward;Sharma, Rajiv P.
与女性相比，男性精神分裂症的发病率更高，阴性症状和认知症状增加，总体病程较差。精神分裂症是一种基因转录和调控异常的疾病。因此，表观遗传学，即研究环境诱导的基因调控变化，可以促进我们对精神分裂症分子基础的理解。外周组蛋白甲基转移酶(HMT)mRNA水平在精神分裂症患者中显著升高，并与症状相关。在这项独立的研究中，提取了74名参与者的外周血淋巴细胞，并测量了临床症状(40名精神分裂症患者(19名女性，21名男性)和34名健康人(19名女性，15名男性))。用逆转录聚合酶链式反应和双抗体夹心酶联免疫吸附试验分别检测HMT(G9α、SETDB1和GLP)基因水平及其对组蛋白H3K9me2的修饰作用。采用双抗体夹心法测定血浆雌二醇水平，并与HMT mRNA进行相关分析。临床症状采用阳性与阴性症状量表(PANSS)和Heinrichs Carpenter生活质量量表(QLS)进行评定。结果表明，男性精神分裂症患者G9α、SETDB1mRNA和H3K9me2蛋白表达水平最高。此外，较高水平的症状和总体较差的生活质量与较高的HMT mRNA和H3K9me2蛋白水平相关，这与性别相关。这些数据支持性别相关的限制性表观基因组在精神分裂症的病因中起作用的假设。这些组蛋白甲基转移酶有可能成为未来小分子药理学的潜在治疗靶点。
When compared to women, men have a higher incidence of schizophrenia, with increases in negative and cognitive symptoms, and an overall poorer disease course. Schizophrenia is conceptualized as a disorder of aberrant gene transcription and regulation. Thus, epigenetics, the study of environmentally induced changes in gene regulation, could advance our understanding of the molecular underpinnings of schizophrenia. Peripheral histone methyltransferase (HMT) mRNA levels have been previously shown to be significantly increased in patients with schizophrenia and correlate with symptomology. In this independent study, peripheral lymphocytes were extracted and clinical symptoms were measured on 74 participants, (40 patients with schizophrenia (19 women, 21 men) and 34 healthy individuals (19 women, 15 men)). HMT (G9α, SETDB1 and GLP) mRNA levels and their resulting histone modification H3K9me2 were measured with RT-PCR and ELISA respectively. Plasma estradiol levels were also measured via ELISA and correlated with HMT mRNA. Clinical symptoms were measured utilizing the Positive and Negative Syndrome Scale (PANSS) and the Heinrichs Carpenter Quality of Life Scale (QLS). The results indicate that men with schizophrenia expressed the highest levels of G9α, SETDB1 mRNA and H3K9me2 protein levels. Additionally, higher levels of symptom presentation and an overall poorer quality of life were correlated with higher HMT mRNA and H3K9me2 protein levels in a sex-dependent pattern. These data support the hypothesis of a sex-dependent restrictive epigenome contributing towards the etiology of schizophrenia. The histone methyltransferases measured here could be potential future therapeutic targets for small molecule pharmacology.
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