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Abstract
BackgroundAutism spectrum disorders (ASDs) likely involve dysregulation of multiple genes related to brain function and development. Abnormalities in individual regulatory small non-coding RNA (sncRNA), including microRNA (miRNA), could have profound effects upon multiple functional pathways. We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC).MethodsWe measured sncRNA expression levels in 34 samples of postmortem brain from STS and PAC to find differentially expressed sncRNA in ASD compared with control cases. For differentially expressed miRNA, we further analyzed their predicted mRNA targets and carried out functional over-representation analysis of KEGG pathways to examine their functional significance and to compare our findings to reported alterations in ASD gene expression.ResultsTwo mature miRNAs (miR-4753-5p and miR-1) were differentially expressed in ASD relative to control in STS and four (miR-664-3p, miR-4709-3p, miR-4742-3p, and miR-297) in PAC. In both regions, miRNA were functionally related to various nervous system, cell cycle, and canonical signaling pathways, including PI3K-Akt signaling, previously implicated in ASD. Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain.ConclusionsAlterations in sncRNA may underlie dysregulation of molecular pathways implicated in autism. sncRNA transcriptional abnormalities in ASD were apparent in STS and in PAC, a brain region not directly associated with core behavioral impairments. Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-015-0029-9) contains supplementary material, which is available to authorized users.
Highlights
Autism spectrum disorders (ASDs) likely involve dysregulation of multiple genes related to brain function and development
Given that changes in gene expression must underlie the clinical phenotype at least to some degree, what might be driving these changes that appear to be region and perhaps even cell specific? Among the many factors that can regulate gene expression—including DNA methylation, transcription factors, and others—we opted to examine small non-coding RNA in this study, including microRNA and small nucleolar RNA. miRNA are of particular interest because, they do not code for protein, they bind sequence-specific sites in target transcripts to regulate expression levels of mRNA and/or modulate protein translation [8]
Small non-coding RNA significantly differed between ASD and controls There were no significant differences in the sex or age of ASD compared to control subjects (P > 0.05, Table 1)
Summary
Autism spectrum disorders (ASDs) likely involve dysregulation of multiple genes related to brain function and development. Part of the answer to this problem appears to be that a variety of etiologically heterogeneous disorders converge on and disrupt key stages of neurodevelopment that affect specific brain regions and molecular pathways. Evidence for this has come in part from pathway analyses of ASD candidate genes and changes of gene expression in brain tissue [2, 3]. Ander et al Molecular Autism (2015) 6:37 genomic and gene expression studies of brain tissue have shown distinct and reproducible changes in transcriptome organization [4], genetic pathways related to neuron function and development [5,6,7], and immune pathways [5] in ASD. Disturbances in a single miRNA could affect hundreds of genes, directly, and many hundreds of genes, indirectly, and would be one way where a single disturbance could dramatically affect complex cellular organization and function
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