Alternative splicing mechanisms orchestrating post-transcriptional gene expression: intron retention and the intron-rich genome of apicomplexan parasites

Abstract

Apicomplexan parasites including Toxoplasma gondii and Plasmodium species have complex life cycles that include multiple hosts and differentiation through several morphologically distinct stages requiring marked changes in gene expression. This review highlights emerging evidence implicating regulation of mRNA splicing as a mechanism to prime these parasites for rapid gene expression upon differentiation. We summarize the most important insights in alternative splicing including its role in regulating gene expression by decreasing mRNA abundance via 'Regulated Unproductive Splicing and Translation'. As a related but less well-understood mechanism, we discuss also our recent work suggesting a role for intron retention for precluding translation of stage specific isoforms of T. gondii glycolytic enzymes. We additionally provide new evidence that intron retention might be a widespread mechanism during parasite differentiation. Supporting this notion, recent genome-wide analysis of Toxoplasma and Plasmodium suggests intron retention is more pervasive than heretofore thought. These findings parallel recent emergence of intron retention being more prevalent in mammals than previously believed, thereby adding to the established roles in plants, fungi and unicellular eukaryotes. Deeper mechanistic studies of intron retention will provide important insight into its role in regulating gene expression in apicomplexan parasites and more general in eukaryotic organisms.

Genome-Wide Transcriptome Analysis Reveals Extensive Alternative Splicing Events in the Protoscoleces of Echinococcus granulosus and Echinococcus multilocularis

“…As one of major fields of enquiry in the post-genomic era, AS has been investigated in an increasing number of species over the past decade (Kalsotra and Cooper, 2011; Filichkin et al, 2015; Lunghi et al, 2016). It has been shown that AS plays a crucial role in enhancing transcriptomic and proteomic diversity, and its prevalence and characteristics vary considerably at many different levels, such as in species, tissues, and developmental stage (Kornblihtt et al, 2013).…”

“…It is noteworthy that intron retention, but not exon skipping, was the predominant AS type in protoscoleces based on our high-coverage poly(A) + RNA-Seq data. The advent of new sequencing technologies and algorithms is providing growing evidence that intron retention is a universal mechanism common to many eukaryotic organisms (Lunghi et al, 2016). By applying a new pipeline for intron-retention detection to high-coverage poly(A) + RNA-Seq data, Braunschweig et al (2014) found that intron retention is far more frequent in mammals than previously believed, affecting transcripts from as many as three-quarters of intron-containing genes.…”

“…In a study by Dvinge and Bradley (2015), it was found that an increase in retained introns is common in most cancer transcriptomes affecting genes involved in RNA processing and nuclear export. Moreover, the identification of increasing numbers of regulated intron-retention events in multi-stage unicellular parasites and plants suggests that these mechanisms can facilitate adaptation to acute host environmental changes, or duly supply key molecules to invade and exploit different ecological niches (Filichkin et al, 2015; Lunghi et al, 2016). The amazingly high frequency of intron retention in protoscoleces of Echinococcus species revealed that intron retention may play crucial roles in the development of the parasite and in host–parasite interaction.…”

Intron‑specific shRNA‑mediated downregulation of survivin and promotion of apoptosis in HeLa cells

“…However, a previous study demonstrated that introns serve a critical role in transcriptional regulation ( 44 ). Introns are not only involved in the formation of microRNAs and small nucleolar RNAs, but also regulate alternative splicing and affect the mRNA level ( 45 ). In the present study, the shRNAs targeting exons and introns effectively inhibited the expression of survivin in HeLa cells and increased the apoptosis rate, inducing marked apoptotic morphological changes.…”

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

“…Studies also have shown that unproductive splicing events prevent mRNA translation (e.g., no-go, non-sense-mediated, and nonstop decay) (32)(33)(34). Over the past decade, more examples of this phenomenon have been revealed, and it has been shown that alternative splicing produces structurally and functionally distinct mRNA and proteins, which enhance transcriptome and proteome diversity in humans considerably (35)(36)(37). Recent studies have indicated that .95% of human genes undergo alternative splicing and that many point mutations that result in human genetic disease have disrupted splicing (38,39).…”