Developmental Dynamics of RNA Translation in the Human Brain

The precise regulation of gene expression is fundamental to neurodevelopment, plasticity, and cognitive function. While several studies have profiled transcription in the developing human brain, there is a gap in our understanding of accompanying translational regulation. We performed ribosome profiling on 73 human prenatal and adult cortex samples. We characterized the translational regulation of annotated open reading frames (ORFs) and identified thousands of previously unknown translation events, including small ORFs that give rise to human- and/or brain-specific microproteins, many of which we independently verified using proteomics. Ribosome profiling in stem cell-derived human neuronal cultures corroborated these findings and revealed that several neuronal activity-induced non-coding RNAs encode previously undescribed microproteins. Physicochemical analysis of brain microproteins identified a class of proteins that contain arginine-glycine-glycine (RGG) repeats and thus may be regulators of RNA metabolism. This resource expands the known translational landscape of the human brain and illuminates previously unknown brain-specific protein products. Ribosome profiling of cultured human embryonic stem cell derived neurons

基因表达的精准调控是神经发育、神经可塑性与认知功能的核心基础。尽管已有多项研究对发育中人脑的转录谱进行了分析，但我们对伴随发生的翻译调控的认知仍存在空白。本研究对73份人类产前及成年大脑皮层样本开展了核糖体谱（ribosome profiling）分析，系统解析了已注释开放阅读框（ORFs）的翻译调控特征，并鉴定出数千个此前未被发现的翻译事件，其中包括可产生人类特异性或脑特异性微蛋白（microproteins）的小型开放阅读框，其中多数通过蛋白质组学手段得到了独立验证。对干细胞诱导的人类神经元培养物开展的核糖体谱分析验证了上述结论，并揭示出若干神经元活动诱导的非编码RNA可编码此前未被报道的微蛋白。对脑内微蛋白的理化特性分析发现了一类含有精氨酸-甘氨酸-甘氨酸（RGG）重复序列的蛋白，这类蛋白可能作为RNA代谢的调控因子。本数据集拓展了目前已知的人类大脑翻译调控全景，并揭示了此前未被发现的脑特异性蛋白产物。针对培养的人类胚胎干细胞诱导神经元的核糖体谱分析