Impact of the Autism-Associated Long Noncoding RNA MSNP1AS on Neuronal Architecture and Gene Expression in Human Neural Progenitor Cells

Jessica J DeWitt; Nicole Grepo; Brent Wilkinson; Oleg V Evgrafov; James A Knowles; Daniel B Campbell

doi:10.3390/genes7100076

Impact of the Autism-Associated Long Noncoding RNA MSNP1AS on Neuronal Architecture and Gene Expression in Human Neural Progenitor Cells

Genes (Basel). 2016 Sep 28;7(10):76. doi: 10.3390/genes7100076.

Authors

Jessica J DeWitt¹, Nicole Grepo², Brent Wilkinson³, Oleg V Evgrafov^{4

5}, James A Knowles^{6

7}, Daniel B Campbell^{8

9}

Affiliations

¹ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. jjdewitt@usc.edu.
² Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. grepo@usc.edu.
³ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. brentwil@usc.edu.
⁴ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. evgrafov@med.usc.edu.
⁵ Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. evgrafov@med.usc.edu.
⁶ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. knowles@med.usc.edu.
⁷ Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. knowles@med.usc.edu.
⁸ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. dbcampbe@med.usc.edu.
⁹ Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. dbcampbe@med.usc.edu.

Abstract

We previously identified the long noncoding RNA (lncRNA) MSNP1AS (moesin pseudogene 1, antisense) as a functional element revealed by genome wide significant association with autism spectrum disorder (ASD). MSNP1AS expression was increased in the postmortem cerebral cortex of individuals with ASD and particularly in individuals with the ASD-associated genetic markers on chromosome 5p14.1. Here, we mimicked the overexpression of MSNP1AS observed in postmortem ASD cerebral cortex in human neural progenitor cell lines to determine the impact on neurite complexity and gene expression. ReNcell CX and SK-N-SH were transfected with an overexpression vector containing full-length MSNP1AS. Neuronal complexity was determined by the number and length of neuronal processes. Gene expression was determined by strand-specific RNA sequencing. MSNP1AS overexpression decreased neurite number and neurite length in both human neural progenitor cell lines. RNA sequencing revealed changes in gene expression in proteins involved in two biological processes: protein synthesis and chromatin remodeling. These data indicate that overexpression of the ASD-associated lncRNA MSNP1AS alters the number and length of neuronal processes. The mechanisms by which MSNP1AS overexpression impacts neuronal differentiation may involve protein synthesis and chromatin structure. These same biological processes are also implicated by rare mutations associated with ASD, suggesting convergent mechanisms.

Keywords: RNA-sequencing; autism; lncRNA; long noncoding RNA; neuronal progenitor; noncoding RNA.

Abstract

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