Objectives: The purpose of this study was to investigate the post-transcriptional gene regulatory networks by miRNA expression profiling of lymphoblastoid cell lines (LCLs) in order to better understand the role of miRNAs in the pathobiology of ASD.
Methods: Global miRNA expression profiling using LCLs derived from 5 autistic individuals and their monozygotic co-twins and/or their siblings were performed using high-throughput miRNA microarray analysis. The potential targets for each miRNA were predicted using miRBase software. An inverse relationship between the transcript levels of the potential target genes and that of the respective regulatory miRNAs in the same LCLs was used to identify miRNAs that could be responsible for the differential gene expression observed between discordant autistic twins and affected-unaffected sib pairs. Biological functions and pathways associated with the potential target genes were analyzed using Ingenuity Pathway Analyses and Pathway Studio 5 software.
Results: The majority of the significantly differentially expressed miRNAs were found to target genes highly involved in neurological functions and disorders. The potential targets, moreover, were also linked to gastrointestinal diseases, inflammatory diseases, and estrogen receptor signaling, including androgen and estrogen metabolism. Among the miRNAs found to be significantly differentially expressed in LCLs were some that were previously identified as brain-specific or brain-related. In addition, a number of the predicted potential target genes were also found to be significantly differentially expressed by cDNA microarray analyses. Novel network prediction analyses of the potential target genes whose transcript levels show an inverse relationship to that of the respective putative regulatory miRNAs reveal association with autism and other co-morbid disorders, e.g., muscular dystrophy and gastrointestinal diseases. Many biological functions implicated in autism, such as memory and synaptic plasticity, were also highlighted.
Conclusions: MiRNA expression profiling using LCLs reveals that post-transcriptional regulation of gene expression by miRNA may be a key factor contributing to the dysregulation of genes associated with neurological functions implicated in the pathophysiology of autism, such as synaptic transmission and plasticity. Moreover, finding brain-specific and brain-related miRNAs differentially expressed in LCLs also suggests the use of LCLs as a surrogate tissue to study miRNAs expression in ASD.
This study was supported by Autism Speaks, Grant #2381.