Elevated Transcription Factor Specificity Protein 1 in Autistic Brains Alters the Expression of Autism Candidate Genes
Elevated Transcription Factor Specificity Protein 1 in Autistic Brains Alters the Expression of Autism Candidate Genes
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DOI：
10.1016/j.biopsych.2011.09.020
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发表时间：
2012-03-01
影响因子：
10.6
通讯作者：
Mori, Norio
中科院分区：
文献类型：
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作者：
Thanseem, Ismail;Anitha, Ayyappan;Mori, Norio
背景资料：基因表达的深刻变化可以由序列特异性转录因子如特异性蛋白1（Sp1）的浓度异常引起。特异性蛋白1结合位点已被报道在涉及自闭症的几个基因的启动子区域。我们假设，功能障碍的Sp1可能会影响多个自闭症候选基因的表达，有助于自闭症heterogeneity of autosity.Methods的异质性：我们评估了任何改变的Sp1和自闭症候选基因的表达在死后的大脑（前扣带回[ACG]，运动皮层，丘脑）的自闭症患者（n = 8）与健康对照组（n = 13）相比。在SK-N-SH神经元cells.Results中研究了用光辉霉素抑制Sp1/DNA结合和用RNAi沉默Sp1后候选基因表达的改变：我们观察到自闭症患者ACG中Sp1的表达升高（p = 0.010）。我们还观察到几个自闭症候选基因的表达改变。GABRB 3、CD 3 N和HTR 2A的表达减少，而CD 38、ITGB 3、MAOA、MECP 2、OXTR和PTEN在自闭症中的表达升高。在SK-N-SH细胞中，在Sp1/DNA结合抑制和Sp1沉默后，OXTR、PTEN和OXTRN的表达降低。结论：转录因子Sp1在孤独症患者的ACG中存在功能障碍。因此，受Sp1调控的潜在自闭症候选基因的表达，特别是OXTR和PTEN，可能会受到影响。由Sp1调节基因介导的不同下游通路，沿着Sp1的环境和细胞内信号相关调节，可以解释与自闭症相关的复杂表型。
Background: Profound changes in gene expression can result from abnormalities in the concentrations of sequence-specific transcription factors like specificity protein 1 (Sp1). Specificity protein 1 binding sites have been reported in the promoter regions of several genes implicated in autism. We hypothesize that dysfunction of Sp1 could affect the expression of multiple autism candidate genes, contributing to the heterogeneity of autism.Methods: We assessed any alterations in the expression of Sp1 and that of autism candidate genes in the postmortem brain (anterior cingulate gyrus [ACG], motor cortex, and thalamus) of autism patients (n = 8) compared with healthy control subjects (n = 13). Alterations in the expression of candidate genes upon Sp1/DNA binding inhibition with mithramycin and Sp1 silencing by RNAi were studied in SK-N-SH neuronal cells.Results: We observed elevated expression of Sp1 in ACG of autism patients (p = .010). We also observed altered expression of several autism candidate genes. GABRB3, RELN, and HTR2A showed reduced expression, whereas CD38, ITGB3, MAOA, MECP2, OXTR, and PTEN showed elevated expression in autism. In SK-N-SH cells, OXTR, PTEN, and RELN showed reduced expression upon Sp1/DNA binding inhibition and Sp1 silencing. The RNA integrity number was not available for any of the samples.Conclusions: Transcription factor Sp1 is dysfunctional in the ACG of autistic brain. Consequently, the expression of potential autism candidate genes regulated by Sp1, especially OXTR and PTEN, could be affected. The diverse downstream pathways mediated by the Sp1-regulated genes, along with the environmental and intracellular signal-related regulation of Sp1, could explain the complex phenotypes associated with autism.