Yen-Ju ChenChia-Ying ChenTe-Lun MaiChih-Fan ChuangYu-Chen ChenSachin Kumar GuptaLaising YenYi-Da WangTrees-Juen Chuang2022-01-252022-01-2520201088-9051https://scholars.lib.ntu.edu.tw/handle/123456789/593644Circular RNAs (circRNAs), a class of long noncoding RNAs, are known to be enriched in mammalian neural tissues. Although 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 postmortem 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 8170 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 show overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were regulated by an up-regulated circRNA (circARID1A) via sponging a down-regulated 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 circRNA regulatory networks in ASD cortex samples. We provided a rich set of ASD-associated circRNA candidates and the corresponding circRNA-microRNA-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.enSPECTRUM DISORDER; SOCIAL-BEHAVIOR; GENE-EXPRESSION; MICE LACKING; REVEALS; BIOGENESIS; TRANSCRIPTOME; INSIGHTS; ABUNDANT; BRAIN[SDGs]SDG311beta hydroxysteroid dehydrogenase 1; circular ribonucleic acid; messenger RNA; microRNA; microRNA 204 3p; neuroligin 1; unclassified drug; vasoactive intestinal polypeptide; messenger RNA; microRNA; animal tissue; Article; astrocyte; autism; brain cortex; brain disease; cell fractionation; cerebellum vermis; comorbidity; controlled study; down regulation; frontal cortex; gene expression; gene expression profiling; genetic risk; genome-wide association study; high throughput sequencing; human; human cell; human tissue; interactions with RNA; major clinical study; memory consolidation; mouse; nerve cell; nonhuman; organoid; postsynaptic density; priority journal; protein expression; RNA sequencing; temporal cortex; transcriptomics; upregulation; autism; brain; cell line; gene expression regulation; genetics; human genome; metabolism; neural stem cell; Astrocytes; Autism Spectrum Disorder; Brain; Cell Line; Gene Expression Regulation; Genome, Human; Humans; MicroRNAs; Neural Stem Cells; Neurons; RNA, Circular; RNA, Messengerjournal article10.1101/gr.255463.119321274162-s2.0-85082517260WOS:000521826300005https://doi.org/10.1101%2Fgr.255463.11970544016