Regulatory characterisation of the schizophrenia-associated CACNA1C proximal promoter and the potential role for the transcription factor EZH2 in schizophrenia aetiology.
Regulatory characterisation of the schizophrenia-associated CACNA1C proximal promoter and the potential role for the transcription factor EZH2 in schizophrenia aetiology.
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DOI：
10.1016/j.schres.2018.02.036
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发表时间：
2018-09
影响因子：
4.5
通讯作者：
Quinn JP
中科院分区：
文献类型：
--
作者：
Billingsley KJ;Manca M;Gianfrancesco O;Collier DA;Sharp H;Bubb VJ;Quinn JP
基因组广泛关联研究确定CACNA 1C基因座与精神分裂症和双相情感障碍都有遗传关联。CACNA 1C编码Cav1.2，Cav1.2是L型电压门控钙通道的四个亚基之一。变异存在于CACNA 1C的非编码区，其与启动子相互作用并且是经验证的表达数量性状位点。使用报告基因构建体，我们证明了CACNA 1C启动子是SH-SY 5 Y神经母细胞瘤细胞系中CACNA 1C活性诱导调节的主要介质。暴露于锂和可卡因的SH-SY 5 Y细胞调节内源性CACNA 1C基因和报告基因构建体中的启动子。启动子的缺失分析表明锂和可卡因的作用都是由近端启动子介导的。在CACNA 1C启动子上的ENCODE ChIP-seq数据的初始询问表明转录因子“zeste同源物2的增强子”（EZH 2）的结合，这与我们的数据一致，即EZH 2的过表达抑制CACNA 1C启动子报告基因表达。来自人脑转录组的阵列数据表明，EZH 2在发育中的大脑中高度表达，但随后在出生和成年后维持在低水平。从PD_NGSAtlas（精神障碍的表观基因组和转录组数据的参考数据库）获得的RNA-seq数据表明，与对照相比，精神分裂症个体的前扣带皮层中EZH 2表达增加了3倍。我们认为EZH 2可能在两个不同的时间点导致精神分裂症的风险，要么是通过破坏发育导致神经发育变化，要么是通过异常激活成人大脑中的表达。
Genomic wide association studies identified the CACNA1C locus as genetically associated with both schizophrenia and bipolar affective disorder. CACNA1C encodes Cav1.2, one of four subunits of L-type voltage gated calcium channels. Variation resides in non-coding regions of CACNA1C which interact with the promoter and are validated expression quantitative trait loci. Using reporter gene constructs we demonstrate the CACNA1C promoter is a major mediator of inducible regulation of CACNA1C activity in the SH-SY5Y neuroblastoma cell line. Exposure of SH-SY5Y cells to lithium and cocaine modulated both the endogenous CACNA1C gene and the promoter in reporter gene constructs. Deletion analysis of the promoter demonstrated the actions of both lithium and cocaine were mediated by the proximal promoter. Initial interrogation of ENCODE ChIP-seq data over the CACNA1C promoter indicated binding of the transcription factor ‘Enhancer of zeste homolog 2’ (EZH2), which was consistent with our data that overexpression of EZH2 repressed CACNA1C promoter reporter gene expression. Array data from the Human Brain Transcriptome demonstrated that EZH2 was highly expressed across the developing brain, but subsequently maintained at low levels after birth and adulthood. RNA-seq data obtained from PD_NGSAtlas, a reference database for epigenomic and transcriptomic data for psychiatric disorders, demonstrated a 3-fold increase in EZH2 expression in the anterior cingulate cortex of individuals with schizophrenia compared to controls. We propose that EZH2 may contribute to schizophrenia risk at two distinct time points either through disruption in development leading to neurodevelopmental changes, or through anomalous reactivation of expression in the adult brain.
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DOI：
10.1038/nrg3413
发表时间：
2013-05
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1083/jcb.200908151
发表时间：
2010-04-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Szulwach KE;Li X;Smrt RD;Li Y;Luo Y;Lin L;Santistevan NJ;Li W;Zhao X;Jin P
通讯作者：
Jin P
精神分裂症基因组相关基因miR137中静止调节的内部启动子的表征。
影响因子：
6.6
作者：
Warburton A;Breen G;Rujescu D;Bubb VJ;Quinn JP
通讯作者：
Quinn JP
影响因子：
7.2
作者：
Karlsgodt KH;Sun D;Cannon TD
通讯作者：
Cannon TD
影响因子：
3.9
作者：
Sun, Jie;Zheng, Guodong;Guo, Zhenhui
通讯作者：
Guo, Zhenhui