Section on Synapse Development and Plasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA.
Systems Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Transl Psychiatry. 2019 Aug 20;9(1):196. doi: 10.1038/s41398-019-0538-y.
Brain development is dependent on programmed gene expression, which is both genetically and epigenetically regulated. Post-transcriptional regulation of gene expression by microRNAs (miRNAs) is essential for brain development. As abnormal brain development is hypothesized to be associated with schizophrenia, miRNAs are an intriguing target for this disorder. The aims of this study were to determine the temporal dynamics of miRNA expression in the human dorsolateral prefrontal cortex (DLPFC), and the relationship between miRNA's temporal expression pattern and dysregulation in schizophrenia. This study used next-generation sequencing to characterize the temporal dynamics of miRNA expression in the DLPFC of 109 normal subjects (second trimester-74 years of age) and miRNA expression changes in 34 schizophrenia patients. Unlike mRNAs, the majority of which exhibits a wave of change in fetuses, most miRNAs are preferentially expressed during a certain period before puberty. It is noted that in schizophrenia patients, miRNAs normally enriched in infants tend to be upregulated, while those normally enriched in prepuberty tend to be downregulated, and the targets of these miRNAs are enriched for genes encoding synaptic proteins and those associated with schizophrenia. In addition, miR-936 and miR-3162 were found to be increased in the DLPFC of patients with schizophrenia. These findings reveal the temporal dynamics of miRNAs in the human DLPFC, implicate the importance of miRNAs in DLPFC development, and suggest a possible link between schizophrenia and dysregulation of miRNAs enriched in infancy and prepuberty.
脑发育依赖于程序化的基因表达，而基因表达既受遗传调控又受表观遗传调控。miRNAs（microRNAs）对基因表达的转录后调控对于脑发育至关重要。由于异常的脑发育被假设与精神分裂症有关，因此 miRNAs 是该疾病的一个有趣的靶点。本研究旨在确定人类背外侧前额叶皮层（DLPFC）中 miRNA 表达的时间动态，以及 miRNA 的时间表达模式与精神分裂症失调之间的关系。本研究使用下一代测序技术来描述 109 名正常受试者（妊娠中期-74 岁）DLPFC 中 miRNA 表达的时间动态，以及 34 名精神分裂症患者的 miRNA 表达变化。与大多数在胎儿中表现出一波变化的 mRNAs 不同，大多数 miRNAs 更倾向于在青春期前的某个特定时期表达。值得注意的是，在精神分裂症患者中，通常在婴儿期富集的 miRNAs 倾向于上调，而那些通常在青春期前富集的 miRNAs 则倾向于下调，这些 miRNA 的靶标富集了编码突触蛋白的基因和与精神分裂症相关的基因。此外，还发现 miR-936 和 miR-3162 在精神分裂症患者的 DLPFC 中增加。这些发现揭示了人类 DLPFC 中 miRNAs 的时间动态，暗示了 miRNAs 在 DLPFC 发育中的重要性，并表明精神分裂症与婴儿期和青春期富集的 miRNAs 失调之间可能存在联系。
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