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

Jessica J. Dewitt, Patrick M. Hecht, Nicole Grepo, Brent Wilkinson, Oleg V. Evgrafov, Kevin V. Morris, James A. Knowles, Daniel B. Campbell

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)375-383
Number of pages9
JournalDevelopmental Neuroscience
Volume38
Issue number5
DOIs
StatePublished - Mar 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience

Keywords

  • Antisense therapy
  • Autism spectrum disorders
  • Long noncoding RNA
  • Noncoding RNA
  • RNA sequencing
  • Small interfering RNA
  • Small noncoding antisense RNA

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