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Bioinformatics analysis of long noncoding RNAs differentially expressed in autism: identification of potential involvement in Staufen-mediated mRNA decay Open Access

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Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. Despite the core symptoms that define ASD, there is considerable heterogeneity in the manifestations and severity of behaviors associated with ASD, thus presenting a major challenge to ‘omics studies directed towards understanding its underlying biology. To reduce heterogeneity in ASD for transcriptomic analyses, our laboratory used multivariate cluster analyses of severity scores on a “gold standard” behavior-based diagnostic instrument to divide individuals with ASD into 4 phenotypically distinct subgroups. Expression profiling of lymphoblastoid cells from three of the four subgroups revealed both distinct as well as overlapping differentially expressed genes relative to controls, of which only 20 transcripts were shared among all three subtypes of ASD. Interestingly, all 20 transcripts were identified as novel, long noncoding RNAs (lncRNAs) of unknown functions. The goal of this study was to employ bioinformatics analyses to identify potential functions of these lncRNAs.An analysis of the sequences of these noncoding transcripts showed that, among these 20 lncRNAs, 5 were found to contain similar Alu elements, which are the most common repetitive sequences in the genome. Published studies showed that lncRNAs with Alu elements can facilitate decay of selected mRNAs by forming dsRNAivstructures with 3’-UTR sequences of mRNAs leading to the recruitment of a protein called Staufen1 (STAU1), a dsRNA binding protein. Subsequently, STAU1 recruits a nonsense-meditated mRNA decay factor UPF1 to cause degradation of the dsRNA helix. Therefore, we postulate that these 5 lncRNA containing Alu elements may play an important role in autism by initiating Staufen-mediated decay (SMD) of selected mRNAs containing 3’-UTR sequences complementary to the Alu elements in the lncRNAs.Here, we show that: 1) some lncRNAs differentially expressed in ASD contain repetitive Alu elements; 2) the Alu-containing regions of the differentially expressed lncRNAs can form dsRNA duplexes with the 3’-UTR regions of a number of different mRNAs; and 3) computer modeling of the interaction of STAU1 and dsRNA duplexes containing the Alu elements of the lncRNAs and 3’-UTRs of several target mRNAs supports potential binding interactions.

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