Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed

Circular RNAs (circRNAs) are an endogenous class of animal RNAs. Despite their abundance, their function and expression in the nervous system are unknown. Therefore, we sequenced RNA from different brain regions, primary neurons, isolated synapses, as well as during neuronal differentiation. Using these and other available data, we discovered and analyzed thousands of neuronal human and mouse circRNAs. circRNAs were extraordinarily enriched in the mammalian brain, well conserved in sequence, often expressed as circRNAs in both human and mouse, and sometimes even detected in Drosophila brains. circRNAs were overall upregulated during neuronal differentiation, highly enriched in synapses, and often differentially expressed compared to their mRNA isoforms. circRNA expression correlated negatively with expression of the RNA-editing enzyme ADAR1. Knockdown of ADAR1 induced elevated circRNA expression. Together, we provide a circRNA brain expression atlas and evidence for important circRNA functions and values as biomarkers. To assess circRNA expression in mammalian brain, we sequenced and analyzed mouse brain regions (hippocampus, cerebellum, prefrontal cortex and olfactory bulb), various neuronal differentiation (mouse P19 and human SH-SY5Y cells) and maturation (mouse cortical neurons) stages, and subcellular compartments in mouse (synaptoneurosomal fraction, cytoplasmic fraction, whole brain lysate).环状RNA（Circular RNAs, circRNAs）是一类内源性动物RNA。尽管它们丰度较高，但其在神经系统中的功能与表达模式仍未明确。为此，我们对不同脑区、原代神经元、分离的突触，以及神经元分化过程中的RNA样本进行了测序。结合此类数据与其他公开可用的数据集，我们发现并分析了数千种人类与小鼠来源的神经元circRNAs。circRNAs在哺乳动物脑中呈现显著富集，序列高度保守，常可在人类与小鼠中以环状RNA形式共同表达，部分甚至可在果蝇脑中检测到。整体而言，circRNAs在神经元分化进程中呈上调趋势，在突触中高度富集，且往往与其对应的mRNA异构体存在差异表达。circRNA的表达水平与RNA编辑酶ADAR1的表达呈负相关；敲低ADAR1可诱导circRNA表达水平升高。综上，本研究构建了circRNA脑表达图谱，并为circRNA作为重要生物标志物的功能与应用价值提供了实验证据。为评估哺乳动物脑中的circRNA表达情况，我们对小鼠脑区（海马体、小脑、前额叶皮层与嗅球）、不同神经元分化阶段（小鼠P19细胞与人类SH-SY5Y细胞）及成熟阶段（小鼠皮层神经元）的样本，以及小鼠的亚细胞组分（突触神经小体组分、细胞质组分、全脑裂解物）进行了测序与分析。