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Autism spectrum disorder (ASD) is a highly pervasive neurodevelopmental and heritable complex disorder, which are characterized by limited social communication, restricted and repetitive interests or behaviors. In this talk, I will introduce the regulatory roles of circular RNAs (circRNAs), a class of long non-coding RNAs produced by pre-mRNA back-splicing, in ASD cortex samples. Our group first performed genome-wide circRNA expression profiling in post-mortem brains from individuals with ASD and controls and identified circRNAs and co-regulated modules that were perturbed in ASD. We identified a rich set of ASD-associated circRNA-microRNA-mRNA interactions and confirmed that some ASD risk genes were indeed regulated by an upregulated circRNA via sponging a downregulated microRNA in human neuronal cells. Furthermore, we investigated the causal relationship between genetic risk variants and transcriptional expression changes in ASD. By integrating RNA-sequencing with genotyping data from autistic brains, we accessed expression quantitative trait loci (eQTL) of circRNAs (circQTLs) that influenced expression of distant genes (trans-eGenes) and constructed 43,372 circQTL-trans-eGene pairs. Mediation test suggested that 19,393 pairs were significantly cis-mediated by expression of circRNAs near the circQTLs; meanwhile, causal inference test (CIT) suggested 1,000 pairs influencing 708 trans-eGenes, wherein trans-eGene expression mediated trans-eQTL effects on ASD diagnosis. The 708 trans-eGenes were enriched for ASD risk genes and overrepresented in neurons in the upper neocortical layer. Integration of mediation test- and CIT-passing pairs further constructed 257 circQTL-circRNA-trans-eGene-ASD propagation paths. These findings increase our understanding of causative biology and cryptic regulatory mechanisms underlying ASD.
Our homepage: http://idv.sinica.edu.tw/trees/.
Prof. Trees-Juen Chuang is the Research Fellow in Genomics Research Center (GRC) of Academia Sinica. He received the Ph.D. degree in Institute of Computer and Information Science of National Chiao Tung University, Taiwan in 1998.After that, he served as the post-doctoral fellow (military service) in the Institute of Biomedical Sciences of Academia Sinica and transferred his research field from pure computer science (image processing and pattern recognition) to biology. He joined GRC as a PI in 2003. His current research interests include comparative and evolutionary genomics/transcriptomics, causative biology, systems biology, and omics data analysis. His research encompasses four components: computer science, statistics, molecular evolution, and molecular biology. His research goal is to investigate the causal relationships between genetic risk variants and transcriptional expression changes in various human complex diseases such as autism spectrum disorder (ASD), Alzheimer's disease (AD), and glioma.