We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
- Authors
Sarachana, Tewarit; Zhou, Rulun; Chen, Guang; Manji, Husseini K.; Hu, Valerie W.
- Abstract
Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by abnormalities in reciprocal social interactions and language development and/or usage, and by restricted interests and repetitive behaviors. Diff erential gene expression of neurologically relevant genes in lymphoblastoid cell lines from monozygotic twins discordant in diagnosis or severity of autism suggested that epigenetic factors such as DNA methylation or microRNAs (miRNAs) may be involved in ASD. Methods: Global miRNA expression profi ling using lymphoblasts derived from these autistic twins and unaff ected sibling controls was therefore performed using high-throughput miRNA microarray analysis. Selected diff erentially expressed miRNAs were confi rmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis, and the putative target genes of two of the confi rmed miRNA were validated by knockdown and overexpression of the respective miRNAs. Results: Diff erentially expressed miRNAs were found to target genes highly involved in neurological functions and disorders in addition to genes involved in gastrointestinal diseases, circadian rhythm signaling, as well as steroid hormone metabolism and receptor signaling. Novel network analyses of the putative target genes that were inversely expressed relative to the relevant miRNA in these same samples further revealed an association with ASD and other co-morbid disorders, including muscle and gastrointestinal diseases, as well as with biological functions implicated in ASD, such as memory and synaptic plasticity. Putative gene targets (ID3 and PLK2) of two RT-PCR-confi rmed brainspecifi c miRNAs (hsa-miR-29b and hsa-miR-219-5p) were validated by miRNA overexpression or knockdown assays, respectively. Comparisons of these mRNA and miRNA expression levels between discordant twins and between casecontrol sib pairs show an inverse relationship, further suggesting that ID3 and PLK2 are in vivo targets of the respective miRNA. Interestingly, the up-regulation of miR-23a and down-regulation of miR-106b in this study refl ected miRNA changes previously reported in post-mortem autistic cerebellum by Abu-Elneel et al. in 2008. This fi nding validates these diff erentially expressed miRNAs in neurological tissue from a diff erent cohort as well as supports the use of the lymphoblasts as a surrogate to study miRNA expression in ASD. Conclusions: Findings from this study strongly suggest that dysregulation of miRNA expression contributes to the observed alterations in gene expression and, in turn, may lead to the pathophysiological conditions underlying autism.
- Subjects
AUTISM spectrum disorders; POST-translational modification; LYMPHOBLASTOID cell lines; NON-coding RNA; GENE targeting
- Publication
Genome Medicine, 2010, Vol 2, Issue 4, p1
- ISSN
1756-994X
- Publication type
Article
- DOI
10.1186/gm144