Dataset Information

Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells.

ABSTRACT: The long noncoding RNA MSNP1AS (moesin pseudogene 1, antisense) is a functional element that was previously associated with autism spectrum disorder (ASD) with genome-wide significance. Expression of MSNP1AS was increased 12-fold in the cerebral cortex of individuals with ASD and 22-fold in individuals with a genome-wide significantly associated ASD genetic marker on chromosome 5p14.1. Overexpression of MSNP1AS in human neuronal cells caused decreased expression of moesin protein, which is involved in neuronal process stability. In this study, we hypothesize that MSNP1AS knockdown impacts global transcriptome levels. We transfected the human neural progenitor cell line SK- N-SH with constructs that caused a 50% suppression of MSNP1AS expression. After 24 h, cells were harvested for total RNA isolation. Strand-specific RNA sequencing analysis indicated altered expression of 1,352 genes, including altered expression of 318 genes following correction for multiple comparisons. Expression of the OAS2 gene was increased >150-fold, a result that was validated by quantitative PCR. Gene ontology analysis of the 318 genes with altered expression following correction for multiple comparisons indicated that upregulated genes were significantly enriched for genes involved in immune response, and downregulated genes were significantly enriched for genes involved in chromatin remodeling. These data indicate multiple transcriptional and translational functions of MSNP1AS that impact ASD-relevant biological processes. Chromatin remodeling and immune response are biological processes implicated by genes with rare mutations associated with ASD. Our data suggest that the functional elements implicated by association of common genetic variants impact the same biological processes, suggesting a possible shared common molecular pathway of ASD.

SUBMITTER: DeWitt JJ

PROVIDER: S-EPMC5759311 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells.

DeWitt Jessica J JJ Hecht Patrick M PM Grepo Nicole N Wilkinson Brent B Evgrafov Oleg V OV Morris Kevin V KV Knowles James A JA Campbell Daniel B DB

Developmental neuroscience 20161229 5

The long noncoding RNA MSNP1AS (moesin pseudogene 1, antisense) is a functional element that was previously associated with autism spectrum disorder (ASD) with genome-wide significance. Expression of MSNP1AS was increased 12-fold in the cerebral cortex of individuals with ASD and 22-fold in individuals with a genome-wide significantly associated ASD genetic marker on chromosome 5p14.1. Overexpression of MSNP1AS in human neuronal cells caused decreased expression of moesin protein, which is invol ...[more]

PMID: 28030860

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Project description:Most of the genetic risk for autism spectrum disorder (ASD) is inherited as common genetic variants, although some rare mutations have been identified in individuals with ASD. Common genetic variants are most parsimoniously identified by genome wide association studies. Genome wide association studies have identified several genetic loci with genome wide association with ASD. However, genome wide association studies only identify regions of the genome associated with phenotypic traits. Identification of the functional elements requires additional experimental evidence. Here, we demonstrate that a genome wide association study locus for ASD on chromosome 20p12.1, rs4141463, implicates a noncoding RNA as a functional element. Although rs4141463 lies within an intron of the protein-coding MACROD2 (MACRO domain containing 2) gene, expression of MACROD2 is neither altered in postmortem temporal cortex of individuals with ASD nor correlated with rs4141463 genotype. Our bioinformatics approaches revealed a noncoding RNA transcript near the autism susceptibility signal, RPS10P2-AS1 (ribosomal protein S10 pseudogene 2 anti-sense 1). In a panel of 15 human tissues, RPS10P2-AS1 was expressed at higher levels than the protein-coding MACROD2 in both fetal temporal cortex and adult peripheral blood. In postmortem temporal cortex, expression of RPS10P2-AS1 was increased 7-fold in individuals with ASD (P = 0.02) and increased 8-fold in individuals with the ASD-associated rs4141463 genotype (P = 0.01). Further, RPS10P2-AS1 expression was increased in human neural progenitor cells exposed to model air pollutants, indicating that both genetic and environmental factors that contribute to ASD increased RPS10P2-AS1 expression. Overexpression of RPS10P2-AS1 in human neural progenitor cells indicated substantial changes in neuronal gene expression. These data indicate that genome-wide significant associations with ASD implicate long noncoding RNAs. Because long noncoding RNAs are more abundant in human brain than protein-coding RNAs, this class of molecules is likely to contribute to ASD risk.

Dataset Information

Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells.

Publications

Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells.

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