Circular RNAs (circRNAs), a class of long noncoding RNAs, are known to be enriched in mammalian neural tissues. While a wide range of dysregulation of gene expression in autism spectrum disorder (ASD) have been reported, the role of circRNAs in ASD remains largely unknown. Here we performed genome-wide circRNA expression profiling in post-mortem brains from individuals with ASD and controls and identified 60 circRNAs and three coregulated modules that were perturbed in ASD. By integrating circRNA, microRNA, and mRNA dysregulation data derived from the same cortex samples, we identified 8,170 ASD-associated circRNA-microRNA-mRNA interactions. Putative targets of the axes were enriched for ASD risk genes and genes encoding inhibitory postsynaptic density (PSD) proteins, but not for genes implicated in monogenetic forms of other brain disorders or genes encoding excitatory PSD proteins. This reflects the previous observation that ASD-derived organoids exhibit overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were regulated by an upregulated circRNA (circARID1A) via sponging a downregulated microRNA (miR-204-3p) in human neuronal cells. Particularly, alteration of NLGN1 expression is known to affect the dynamic processes of memory consolidation and strengthening. To the best of our knowledge, this is the first systems-level view of landscape of circRNA regulatory networks in ASD cortex samples. We provided a rich set of ASD-associated circRNA candidates and the corresponding circRNA-miRNA-mRNA axes, particularly those involving ASD risk genes. Our findings thus support a role for circRNA dysregulation and the corresponding circRNA-microRNA-mRNA axes in ASD pathophysiology.

中文翻译：

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全基因组的自闭症中环状RNA失调和相应环状RNA-microRNA-mRNA调控轴的综合分析。

环状RNA（circRNA）是一类长的非编码RNA，已知在哺乳动物神经组织中富集。尽管自闭症谱系障碍（ASD）中基因表达的广泛失调已被报道，但是circRNA在ASD中的作用仍然未知。在这里，我们在具有ASD和对照的个体的死后大脑中进行了全基因组circRNA表达谱分析，并确定了60个circRNA和三个在ASD中受到干扰的调节模块。通过整合来自相同皮层样品的circRNA，microRNA和mRNA失调数据，我们确定了8,170个与ASD相关的circRNA-microRNA-mRNA相互作用。轴的推定靶点富含ASD风险基因和编码抑制性突触后密度（PSD）蛋白的基因，但不适用于与其他脑部疾病的单基因形式有关的基因或编码兴奋性PSD蛋白的基因。这反映了先前的观察结果，即ASD衍生的类器官表现出抑制神经元的过度产生。我们进一步证实，某些ASD风险基因（NLGN1，STAG1，HSD11B1，VIP和UBA6）是通过在人神经元细胞中掺入下调的microRNA（miR-204-3p）而由上调的circRNA（circARID1A）调节的。特别是，已知NLGN1表达的改变会影响记忆整合和增强的动态过程。据我们所知，这是ASD皮质样品中circRNA调控网络格局的第一个系统级视图。我们提供了丰富的ASD相关circRNA候选集和相应的circRNA-miRNA-mRNA轴，特别是涉及ASD风险基因的轴。