Integrated microRNA–mRNA Expression Profiling Identifies Novel Targets and Networks Associated with Autism

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, with mutations in hundreds of genes contributing to its risk. Herein, we studied lymphoblastoid cell lines (LCLs) from children diagnosed with autistic disorder (n = 10) and controls (n = 7) using RNA and miRNA sequencing profiles. The sequencing analysis identified 1700 genes and 102 miRNAs differentially expressed between the ASD and control LCLs (p ≤ 0.05). The top upregulated genes were GABRA4, AUTS2, and IL27, and the top upregulated miRNAs were hsa-miR-6813-3p, hsa-miR-221-5p, and hsa-miR-21-5p. The RT-qPCR analysis confirmed the sequencing results for randomly selected candidates: AUTS2, FMR1, PTEN, hsa-miR-15a-5p, hsa-miR-92a-3p, and hsa-miR-125b-5p. The functional enrichment analysis showed pathways involved in ASD control proliferation of neuronal cells, cell death of immune cells, epilepsy or neurodevelopmental disorders, WNT and PTEN signaling, apoptosis, and cancer. The integration of mRNA and miRNA sequencing profiles by miRWalk2.0 identified correlated changes in miRNAs and their targets’ expression. The integration analysis found significantly dysregulated miRNA–gene pairs in ASD. Overall, these findings suggest that mRNA and miRNA expression profiles in ASD are greatly altered in LCLs and reveal numerous miRNA–gene interactions that regulate critical pathways involved in the proliferation of neuronal cells, cell death of immune cells, and neuronal development.

miRNAs as biomarkers of autism spectrum disorder: a systematic review and meta-analysis

“…miRNA was measured in lymphoblastoid cell lines in three studies [14,22,29], five studies measured miRNA in postmortem cerebral cortex tissues [2,15,[30][31][32], one study used cells from the olfactory mucosa [18], thirteen studies used serum [7,19,24,[33][34][35][36][37][38][39][40][41][42], and five studies used saliva [8,16,[43][44][45]. A recent narrative review [46] found that the miR-151a, miR-146a, and miR-27a-30 are dysregulated in people with ASD and are replicated in more than one tissue.…”

Serum Extracellular Vesicle-Derived hsa-miR-2277-3p and hsa-miR-6813-3p Are Potential Biomarkers for Major Depression: A Preliminary Study

“…The expression of hsa-miR-6813-3p and hsa-miR-2277-3p was significantly lower in the MD group than in the healthy control group. Previous work has reported that miR-6813-3p is involved in ASD [ 44 ]. Prior research has also shown that miR-2277-3p is involved in colon cancer cells [ 45 ].…”

Identification of miRNAs in extracellular vesicles as potential diagnostic markers for pediatric epilepsy and drug-resistant epilepsy via bioinformatics analysis

“…Li et al reported that miR-199a-3p is dysregulated in neurons of children with epilepsy, which is regulated by lncRNA-TUBG1 and associated with neuron apoptosis and biological behaviors ( 50 ). Moreover, miR-21-5p has been implicated in a variety of neurological disease, i.e., epilepsy, dementia, Alzheimer's disease, and autism, along with regulating apoptosis of hippocampal neurons ( 17 , 51 – 53 ). It has been suggested by the findings that these four miRNAs may be crucially involved in epileptogenesis.…”

“…Research by Johnson et al suggested that the reduced expression of miR-1307-3p in the saliva of children who experienced concussion predicted a significantly high probability of conversion to (50). Moreover, miR-21-5p has been implicated in a variety of neurological disease, i.e., epilepsy, dementia, Alzheimer's disease, and autism, along with regulating apoptosis of hippocampal neurons (17,(51)(52)(53). It has been suggested by the findings that these four miRNAs may be crucially involved in epileptogenesis.…”