Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism

Abstract

Circular 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 ASDassociated 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.

Recent Progress on Relevant microRNAs in Autism Spectrum Disorders

“…We summarize and discuss recent studies on miRNAs related to ASD, and explore potential methods for diagnosing and treating ASD based on miRNAs. For information on miRNAs in ASD animal models, please read Schepici et al, 2019 [ 52 ]; for synergy of miRNAs in ASD and allergic dermatitis, refer to Tonacci et al, 2019 [ 53 ]; for mutations of miRNAs in ASD patients, please refer to Fregeac et al, 2016 [ 54 ]; for dysregulation of circRNA in patients with ASD and the corresponding pathogenic role of circRNA–microRNA–mRNA regulation axes in ASD, please refer to Chen et al, 2020 [ 55 ]; for information on dysregulated miRNAs in ASD patients as potential diagnostic biomarkers and potential therapeutic targets, please refer to Anitha and Thanseem, 2015 [ 56 ].…”

The Secret Garden of Neuronal circRNAs

“…Most studies on circRNA expression in neuronal diseases correlates the circRNA expression profile with miRNA and mRNA profiles ( Table 2 ). Disease-regulatory networks of circRNA-miRNA-mRNA are bioinformatically extracted, by the identification of microRNAs targeting the circRNA sequences with an opposite differential expression, and the miRNA target mRNA with a regulation similar to circRNA [ 81 , 90 , 93 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ]. Based on the presence of one to seven miRNA target sequences on the circRNA, the decrease in miRNA levels is associated with the observed increase in the cognate circRNA levels through a sponge mechanism, in which circRNAs act as competing endogenous RNAs [ 124 , 125 , 126 , 127 ].…”

Insights Into Translatomics in the Nervous System

“…Zyryanova et al, 2018 Regulatory RNAs Inhibit translation, mediated by microRNAs decreasing protein levels. Schratt et al, 2006;Murphy et al, 2017;Zhang H. et al, 2018;Chen et al, 2020 IncRNAs and circRNAs function as competing endogenous RNAs by sponging microRNAs in neuronal cells.…”

“…miR-144-3p represses translation and is linked to the rescue of anxiety-like behavior ( Murphy et al, 2017 ). Mounting evidence indicate that lnc-RNA (long non-coding RNAs) and circRNAs (circular RNAs) act as competing endogenous RNAs by sponging microRNAs in neuronal cells ( Zhang H. et al, 2018 ; Chen et al, 2020 ). FMRP (fragile X mental retardation protein), an RNA binding protein, appears to directly bind to the 80S ribosome, thereby repressing translation of target mRNAs, and has been linked to autism ( Darnell et al, 2011 ; Chen et al, 2014 ).…”