Transcriptional Changes following Cellular Knockdown of the Schizophrenia Risk Gene SETD1A Are Enriched for Common Variant Association with the Disorder.
Transcriptional Changes following Cellular Knockdown of the Schizophrenia Risk Gene SETD1A Are Enriched for Common Variant Association with the Disorder.
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DOI：
10.1159/000497181
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发表时间：
2019-04-01
期刊：
影响因子：
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通讯作者：
Hill, Matthew J
中科院分区：
文献类型：
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作者：
Cameron, Darren;Blake, Derek J;Hill, Matthew J
SETD1A的功能突变缺失是精神分裂症外显子组测序研究中出现的第一个实验范围内的重大发现。尽管已知SETD1A编码组蛋白甲基转移酶，但迄今为止，尚不清楚SETD1A活性降低对神经细胞中基因表达的影响。为了探索SETD1A基因扰动可能导致精神分裂症风险的转录变化，我们对一种常用的人类神经母细胞瘤细胞系进行了全基因组基因表达谱分析，在这种细胞系中，通过RNA干扰（RNAi）实验降低了SETD1A的表达。我们发现，与对照组相比，在两种不同的RNAi条件下，1031个基因表达发生了显著变化，包括对已知神经发育重要性基因（如DCX和DLX5）的影响。SETD1A敲低后差异表达的基因被富集，用于注释代谢途径、肽酶调节活性和整合素介导的细胞粘附调节。此外，与精神分裂症相关的常见变异富集了差异表达基因，这表明这种罕见的精神分裂症危险因素与更普遍的精神分裂症易感性变异之间存在一定程度的分子趋同。
Loss of function mutations in SETD1A are the first experiment-wide significant findings to emerge from exome sequencing studies of schizophrenia. Although SETD1A is known to encode a histone methyltransferase, the consequences of reduced S ETD1A activity on gene expression in neural cells have, to date, been unknown. To explore transcriptional changes through which genetic perturbation of SETD1A could confer risk for schizophrenia, we have performed genome-wide gene expression profiling of a commonly used human neuroblastoma cell line in which SETD1A expression has been experimentally reduced using RNA interference (RNAi). We identified 1,031 gene expression changes that were significant in two separate RNAi conditions compared with control, including effects on genes of known neurodevelopmental importance such as DCX and DLX5. Genes that were differentially expressed following SETD1A knockdown were enriched for annotation to metabolic pathways, peptidase regulator activity and integrin-mediated regulation of cell adhesion. Moreover, differentially expressed genes were enriched for common variant association with schizophrenia, suggesting a degree of molecular convergence between this rare schizophrenia risk factor and susceptibility variants for the disorder operating more generally.