Genome-wide differential expression of synaptic long noncoding RNAs in autism spectrum disorder.

X Zhao,W T Brown,S Jiang,Y Wang,P Wang,Q Chen,C Shen,X Tao,M Zhong,X Dong,M Flory,N Zhong,W Ju,J Zhong,Y Yu

doi:10.1038/tp.2015.144

Abstract

A genome-wide differential expression of long noncoding RNAs (lncRNAs) was identified in blood specimens of autism spectrum disorder (ASD). A total of 3929 lncRNAs were found to be differentially expressed in ASD peripheral leukocytes, including 2407 that were upregulated and 1522 that were downregulated. Simultaneously, 2591 messenger RNAs (mRNAs), including 1789 upregulated and 821 downregulated, were also identified in ASD leukocytes. Functional pathway analysis of these lncRNAs revealed neurological pathways of the synaptic vesicle cycling, long-term depression and long-term potentiation to be primarily involved. Thirteen synaptic lncRNAs, including nine upregulated and four downregulated, and 19 synaptic mRNAs, including 12 upregulated and seven downregulated, were identified as being differentially expressed in ASD. Our identification of differential expression of synaptic lncRNAs and mRNAs suggested that synaptic vesicle transportation and cycling are important for the delivery of synaptosomal protein(s) between presynaptic and postsynaptic membranes in ASD. Finding of 19 lncRNAs, which are the antisense, bi-directional and intergenic, of HOX genes may lead us to investigate the role of HOX genes involved in the development of ASD. Discovery of the lncRNAs of SHANK2-AS and BDNF-AS, the natural antisense of genes SHANK2 and BDNF, respectively, indicates that in addition to gene mutations, deregulation of lncRNAs on ASD-causing gene loci presents a new approach for exploring possible epigenetic mechanisms underlying ASD. Our study also opened a new avenue for exploring the use of lncRNA(s) as biomarker(s) for the early detection of ASD.

Highlights

Autism spectrum disorder (ASD) has a reported prevalence of 1 in 68 children in the United States.[1]
3 RESULTS Differential expression profiles of long noncoding RNA (lncRNA) and messenger RNA (mRNA) A total of 3929 lncRNAs were identified as differentially expressed in Chinese ASD peripheral blood cells, including 2407 that were upregulated and 1522 that were downregulated
We presented metabolic pathways (Figure 1) that define peripheral blood lncRNAs that are differentially expressed in ASD

Summary

Introduction

Autism spectrum disorder (ASD) has a reported prevalence of 1 in 68 children in the United States.[1]. Mutations of many genes, including NLGN3, NLGN4, NRXN1, SHANK2, SHANK3 and PTCHD1, have been associated with ASD,[2,3] metabolic, infectious, inflammatory and other environmental factors have been implicated in the pathogenesis of ASD.[4,5,6,7,8,9] We previously determined that hypermethylation of the ENO2 gene is present in 15% of children with ASD,[10] indicating that epigenetic factor(s) may contribute to the etiology of ASD.[3,11] In addition, as transcriptional and posttranscriptional regulators, both microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have been reported to be involved in ASD as well as in many other neurological disorders.[12,13,14,15,16,17,18,19,20,21] Overexpression and knockdown studies have shown that lncRNAs have important roles in regulating a variety of processes, including splicing,[22] transcription,[23] localization[24] and the organization of subcellular compartments.[25,26,27,28,29,30,31] Underscoring the importance of lncRNAs’ regulatory roles is their emergence as essential components in the etiology of many disorders, and of complex diseases in particular, for which genetic and environmental interactions have key roles.[31,32,33,34]

Methods

Results

Conclusion