Evidence for genetic regulation of mRNA expression of the dosage-sensitive gene retinoic acid induced-1 (RAI1) in human brain.
Evidence for genetic regulation of mRNA expression of the dosage-sensitive gene retinoic acid induced-1 (RAI1) in human brain.
复制标题
人脑中剂量敏感基因诱导1（RAI1）mRNA表达的遗传调节的证据。
DOI：
10.1038/srep19010
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发表时间：
2016-01-08
影响因子：
4.6
通讯作者：
Saffen D
中科院分区：
文献类型：
--
作者：
Chen L;Tao Y;Song F;Yuan X;Wang J;Saffen D
RAI 1（视黄酸诱导-1）是一种剂量敏感基因，当突变或缺失时会导致Smith-Magenis综合征（SMS），当复制时会导致Potocki-Lupski综合征（PTLS），在这两种综合征中通常观察到精神病学特征。然而，常见的遗传变异如何调节该基因尚不清楚。本研究发现，中国人前额叶和颞叶皮层RAI 1 mRNA的表达与RAI 1 5′-上游区常见的单核苷酸多态性（SNP）基因型相关。使用基因型插补、“R2-Δ2”分析和来自RegulomeDB数据库的数据，我们将SNPs rs 4925102和rs 9907986确定为可能的调控变体，占两个脑区RAI 1 mRNA表达变异的约30-40%。具体而言，预测rs 4925102和rs 9907986分别破坏视黄酸RXR-RAR受体和转录因子DEAF 1（变形表皮自动调节因子-1）的结合。与这些预测一致，我们在染色质免疫沉淀试验中观察到RXRα和RARα与预测的RAI 1靶点的结合。视黄酸对中枢神经系统的早期发育至关重要，而DEAF 1与智力残疾有关。RAI 1 mRNA表达的显著部分是受遗传控制的，这一观察结果提出了一种可能性，即常见的RAI 1 5′-区域调控变体更普遍地导致精神疾病。
RAI1 (retinoic acid induced-1) is a dosage-sensitive gene that causes Smith-Magenis syndrome (SMS) when mutated or deleted and Potocki-Lupski Syndrome (PTLS) when duplicated, with psychiatric features commonly observed in both syndromes. How common genetic variants regulate this gene, however, is unknown. In this study, we found that RAI1 mRNA expression in Chinese prefrontal and temporal cortex correlate with genotypes of common single nucleotide polymorphisms (SNPs) located in the RAI1 5′-upstream region. Using genotype imputation, “R2-Δ2” analysis, and data from the RegulomeDB database, we identified SNPs rs4925102 and rs9907986 as possible regulatory variants, accounting for approximately 30–40% of the variance in RAI1 mRNA expression in both brain regions. Specifically, rs4925102 and rs9907986 are predicted to disrupt the binding of retinoic acid RXR-RAR receptors and the transcription factor DEAF1 (Deformed epidermal autoregulatory factor-1), respectively. Consistent with these predictions, we observed binding of RXRα and RARα to the predicted RAI1 target in chromatin immunoprecipitation assays. Retinoic acid is crucial for early development of the central neural system, and DEAF1 is associated with intellectual disability. The observation that a significant portion of RAI1 mRNA expression is genetically controlled raises the possibility that common RAI1 5′-region regulatory variants contribute more generally to psychiatric disorders.