GAD1 alternative transcripts and DNA methylation in human prefrontal cortex and hippocampus in brain development, schizophrenia.
GAD1 alternative transcripts and DNA methylation in human prefrontal cortex and hippocampus in brain development, schizophrenia.
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DOI：
10.1038/mp.2017.105
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发表时间：
2018-06
影响因子：
11
通讯作者：
Hyde TM
中科院分区：
文献类型：
--
作者：
Tao R;Davis KN;Li C;Shin JH;Gao Y;Jaffe AE;Gondré-Lewis MC;Weinberger DR;Kleinman JE;Hyde TM
基因变异和子宫内或出生后不久的不良环境事件可能导致大脑发育异常，增加患精神分裂症的风险。γ-氨基丁酸（γ-aminobutyric acid，GABA）是哺乳动物脑内主要的抑制性神经递质，在脑的正常发育中起着重要作用。GABA的合成受两种谷氨酸脱羧酶（GAD）基因（GAD 1和GAD 2）衍生的酶控制，这两种基因均产生转录本亚型。虽然全长GAD 1转录本（GAD 67）已被牵连在精神分裂症的神经病理学，GAD 1在人脑中的转录本结构尚未得到充分的表征。在这项研究中，我们使用RNA测序和PCR技术，报告发现10个新的转录本GAD 1在人脑中。四种新的GAD 1转录物（8A、8B、I80和I86）的表达水平显示出与全长GAD 1转录物的表达显著相关的寿命轨迹表达模式。此外，在假定的GAD 1启动子内的两个CpG位点的甲基化水平与精神分裂症风险SNP rs3749034和DLPFC中GAD 25的表达显著相关。此外，自杀和/或尼古丁暴露阳性的精神分裂症患者DLPFC中全长GAD 1表达显著较高。GAD 1的选择性剪接和表观遗传状态似乎在GAD 1表达的发育概况中发挥作用，并可能导致精神分裂症患者PFC和海马中GABA功能障碍。
Genetic variations and adverse environmental events in utero or shortly after birth can lead to abnormal brain development and increased risk of schizophrenia. γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, plays a vital role in normal brain development. GABA synthesis is controlled by enzymes derived from two glutamic acid decarboxylase (GAD) genes, GAD1 and GAD2, both of which produce transcript isoforms. While the full-length GAD1 transcript (GAD67) has been implicated in the neuropathology of schizophrenia, the transcript structure of GAD1 in the human brain has not been fully characterized. In this study, with the use of RNA sequencing and PCR technologies, we report the discovery of 10 novel transcripts of GAD1 in the human brain. Expression levels of four novel GAD1 transcripts (8A, 8B, I80, and I86) showed a life span trajectory expression pattern that is anticorrelated with the expression of the full-length GAD1 transcript. In addition, methylation levels of two CpG loci within the putative GAD1 promoter were significantly associated with the schizophrenia-risk SNP rs3749034 and with the expression of GAD25 in DLPFC. Moreover, schizophrenia patients who had completed suicide and/or were positive for nicotine exposure had significantly higher full-length GAD1 expression in the DLPFC. Alternative splicing of GAD1 and epigenetic state appear to play roles in the developmental profile of GAD1 expression and may contribute to GABA dysfunction in the PFC and hippocampus of patients with schizophrenia.
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影响因子：
2.6
作者：
Lynex CN;Carr IM;Leek JP;Achuthan R;Mitchell S;Maher ER;Woods CG;Bonthon DT;Markham AF
通讯作者：
Markham AF
影响因子：
5
作者：
Lu, Kwok-Tung;Wu, Chang-Yen;Yang, Yi-Ling
通讯作者：
Yang, Yi-Ling
DOI：
10.1073/pnas.89.6.2115
发表时间：
1992-03-15
影响因子：
11.1
作者：
BU, DF;ERLANDER, MG;TOBIN, AJ
通讯作者：
TOBIN, AJ
影响因子：
16.2
作者：
ERLANDER, MG;TILLAKARATNE, NJK;TOBIN, AJ
通讯作者：
TOBIN, AJ
影响因子：
5.8
作者：
Aryee, Martin J.;Jaffe, Andrew E.;Irizarry, Rafael A.
通讯作者：
Irizarry, Rafael A.