Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function [RNA-seq]

Hundreds of circular RNAs (circRNAs) are highly abundant in the mammalian brain, often with conserved expression. Here we show that the circRNA Cdr1as is massively bound by the microRNAs (miRNAs) miR-7 and miR-671 in human and mouse brains. When the Cdr1as locus was removed from the mouse genome, knockout animals displayed impaired sensorimotor gating-a deficit in the ability to filter out unnecessary information-which is associated with neuropsychiatric disorders. Electrophysiological recordings revealed dysfunctional synaptic transmission. Expression of miR-7 and miR-671 was specifically and posttranscriptionally misregulated in all brain regions analyzed. Expression of immediate early genes such as Fos, a direct miR-7 target, was enhanced in Cdr1as-deficient brains, providing a possible molecular link to the behavioral phenotype. Our data indicate an in vivo loss-of-function circRNA phenotype and suggest that interactions between Cdr1as and miRNAs are important for normal brain function. We performed polyA-selected RNA sequencing for three knockout and three wild type replicates in four brain regions - cerebellum, cortex, hippocampus and olfactory bulb.哺乳动物大脑中存在大量高丰度表达的环状RNA（circRNAs），且其表达常具有保守性。本研究证实，在人类与小鼠大脑中，环状RNA Cdr1as可大量结合微小RNA（miRNAs）miR-7与miR-671。将小鼠基因组中的Cdr1as基因座敲除后，基因敲除小鼠出现感觉运动门控功能受损——即过滤无关信息的能力存在缺陷，该表型与神经精神疾病密切相关。电生理记录结果显示其突触传递功能异常。在所检测的全部脑区中，miR-7与miR-671的表达均出现特异性转录后失调。作为miR-7直接靶标的即刻早期基因Fos等的表达在Cdr1as缺陷型小鼠大脑中显著上调，这为该行为表型提供了潜在的分子关联机制。本研究数据揭示了环状RNA的体内功能缺失表型，并表明Cdr1as与微小RNA的相互作用对于维持正常脑功能至关重要。我们对4个脑区（小脑、大脑皮层、海马体与嗅球）的3例基因敲除样本与3例野生型生物学重复样本进行了聚腺苷酸选择性RNA测序。