Abstract
Increasing evidence suggests that noncoding RNAs play key roles in cellular processes, particularly in the brain. The present study used RNA sequencing to identify the transcriptional landscape of two human neural progenitor cell lines, SK-N-SH and ReNcell CX, as they differentiate into human cortical projection neurons. Protein coding genes were found to account for 54.8 and 57.0% of expressed genes, respectively, and alignment of RNA sequencing reads revealed that only 25.5–28.1% mapped to exonic regions of the genome. Differential expression analysis in the two cell lines identified altered gene expression in both protein coding and noncoding RNAs as they undergo neural differentiation with 222 differentially expressed genes observed in SK-N-SH cells and 19 differentially expressed genes in ReNcell CX. Interestingly, genes showing differential expression in SK-N-SH cells are enriched in genes implicated in autism spectrum disorder, but not in gene sets related to cancer or Alzheimer's disease. Weighted gene co-expression network analysis (WGCNA) was used to detect modules of co-expressed protein coding and noncoding RNAs in SK-N-SH cells and found four modules to be associated with neural differentiation. These modules contain varying levels of noncoding RNAs ranging from 10.7 to 49.7% with gene ontology suggesting roles in numerous cellular processes important for differentiation. These results indicate that noncoding RNAs are highly expressed in human neural progenitor cells and likely hold key regulatory roles in gene networks underlying neural differentiation and neurodevelopmental disorders.
Highlights
Neural differentiation is a complex biological process requiring precise regulation of gene expression
The human neural progenitor cell lines, SK-N-SH and ReNcell CX, were used to measure gene expression as they differentiate into cortical projection neurons
It was evident that ReNcell CX cells collected at the 72 h time-point were more mature than the cells collected at the earlier time-point (Supplementary Figure 2) indicating that these cells are in distinct stages of neural differentiation at these two collection time-points
Summary
Neural differentiation is a complex biological process requiring precise regulation of gene expression. The molecular mechanisms underlying this transcriptional control remain largely unknown. It is understood that most of the genome is transcribed with less than 2% encoding for protein resulting in a vast and largely uncharacterized landscape of non-protein coding RNAs Once thought to be transcriptional noise, these noncoding RNAs are emerging as key regulatory elements of gene expression. While several noncoding RNAs have been shown to be important in various biological processes, including cell differentiation (Morris and Mattick, 2014), the functions of most noncoding RNA transcripts are unknown
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