The DPYSL2 gene connects mTOR and schizophrenia.
The DPYSL2 gene connects mTOR and schizophrenia.
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DOI：
10.1038/tp.2016.204
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发表时间：
2016-11-01
影响因子：
6.8
通讯作者：
Avramopoulos D
中科院分区：
文献类型：
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作者：
Pham X;Song G;Lao S;Goff L;Zhu H;Valle D;Avramopoulos D
我们之前报道了 DPYSL2 的 5'-非翻译重复序列 (UTR) 处的精神分裂症相关多态性 CT 二核苷酸重复序列 (DNR)，它响应哺乳动物雷帕霉素靶标 (mTOR) 信号，在报告基因检测中具有等位基因差异。现在，通过微阵列分析，我们发现 DNR 等位基因与特定蛋白质（包括 mTOR 相关蛋白质 HuD/ELAVL4）的相互作用存在差异。我们通过电泳迁移率变动分析确认了与 HuD 和其他已知 mTOR 效应子的差异结合。我们通过 CRISPR/Cas9 编辑 HEK293 细胞，使其携带精神分裂症风险变异 (13DNR)，并观察到相应的 CRMP2 亚型显着减少。这些编辑过的细胞证实了对 mTOR 抑制剂的反应，并显示出细胞投射的两倍缩短。通过 RNA-seq 对这些修饰细胞进行的转录组分析显示，12.7% 的表达转录本发生了变化，错误发现率为 0.05。这些转录本富含免疫相关基因，与精神分裂症相关基因 ZNF804A 修饰的基因显着重叠，并且具有与抗精神病药物所见相反的表达特征。我们的结果支持 DPYSL2 DNR 的功能重要性以及 mTOR 信号在精神分裂症中的作用。
We previously reported a schizophrenia-associated polymorphic CT di-nucleotide repeat (DNR) at the 5′-untranslated repeat (UTR) of DPYSL2, which responds to mammalian target of Rapamycin (mTOR) signaling with allelic differences in reporter assays. Now using microarray analysis, we show that the DNR alleles interact differentially with specific proteins, including the mTOR-related protein HuD/ELAVL4. We confirm the differential binding to HuD and other known mTOR effectors by electrophoretic mobility shift assays. We edit HEK293 cells by CRISPR/Cas9 to carry the schizophrenia risk variant (13DNR) and observe a significant reduction of the corresponding CRMP2 isoform. These edited cells confirm the response to mTOR inhibitors and show a twofold shortening of the cellular projections. Transcriptome analysis of these modified cells by RNA-seq shows changes in 12.7% of expressed transcripts at a false discovery rate of 0.05. These transcripts are enriched in immunity-related genes, overlap significantly with those modified by the schizophrenia-associated gene, ZNF804A, and have a reverse expression signature from that seen with antipsychotic drugs. Our results support the functional importance of the DPYSL2 DNR and a role for mTOR signaling in schizophrenia.