Abstract
The central nervous system has enormously complex cellular diversity with hundreds of distinct cell types, yet alternative splicing features in single cells of important cell types at neurogenic regions are not well understood. By employing in silico analysis, we systematically identified 3,611 alternative splicing events from 1,908 genes in 28 single-cell transcriptomic data of adult mouse ependymal and subependymal regions, and found that single-cell RNA-seq has the advantage in uncovering rare splicing isoforms compared to bulk RNA-seq at the population level. We uncovered that the simultaneous presence of multiple isoforms from the same gene in a single cell is prevalent, and quiescent stem cells, activated stem cells, and neuroblast cells exhibit high heterogeneity of splicing variants. Furthermore, we also demonstrated the existence of novel bicistronic transcripts in quiescent stem cells.
Highlights
Alternative splicing (AS) events of precursor mRNAs are widespread in eukaryotic organisms and enable cells to generate vast protein diversity from a limited number of genes (Gilbert, 1978; Pan et al, 2008; Barbosa-Morais et al, 2012)
To identify AS events of individual cell types in the subventricular zone (SVZ) region, we performed an isoform identification pipeline to analyze transcriptomic data derived from 28 single-cell samples which we have obtained previously (Luo et al, 2015) from adult mouse CD133 positive and negative ependymal/subependymal cells
All the 3,611 AS events identified belong to different categories (Figure 1A) of local splicing patterns: alternative 3′ acceptor sites (AA), alternative 5’ donor sites (AD), alternative promoter (AP), alternative terminator (AT), exon skipping (ES), mutually exclusive exons (ME), and retention intron (RI)
Summary
Alternative splicing (AS) events of precursor mRNAs are widespread in eukaryotic organisms and enable cells to generate vast protein diversity from a limited number of genes (Gilbert, 1978; Pan et al, 2008; Barbosa-Morais et al, 2012). It is established that AS events play diversified regulation roles such as neural cell differentiation, neuronal migration, synapse formation, and brain development in the central nervous system (CNS) (Yano et al, 2010; Grabowski, 2011; Zheng et al, 2012; Shin and Kim, 2013; Mauger et al, 2015). Disruptions in the splicing machinery can result in neurodegeneration (Polymenidou et al, 2011) These findings emphasize the importance of characterizing AS events in CNS tissues and understanding its spatiotemporal and dynamic regulations. Previous population-based studies revealed characteristics and spatiotemporal regulation of AS in the CNS (Jelen et al, 2007; Yano et al, 2010; Grabowski, 2011; Zheng et al, 2012; Shin and Kim, 2013; Mauger et al, 2015; Tilgner et al, 2015; Suzuki et al, 2017; Jackson et al, 2018; Weyn-Vanhentenryck et al, 2018). The CNS has enormously complex cellular diversity with hundreds of distinct cell types, while population-based AS analyses of bulk tissues with heterogeneous cellular composition reveal
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