Noncoding RNAs in Apicomplexan Parasites: An Update

Abstract

Recent breakthroughs in high-throughput technologies, transcriptomics, and advances in our understanding of gene regulatory networks have enhanced our perspective on the complex interplay between parasite and host. Noncoding RNA molecules have been implicated in critical roles covering a broad range of biological processes in the Apicomplexa. Processes that are affected range from parasite development to host-parasite interactions and include interactions with epigenetic machinery and other regulatory factors. Here we review recent progress involving noncoding RNAs and their functions in the Apicomplexa, with a focus on three parasites: Plasmodium, Toxoplasma, and Cryptosporidium. We discuss the limitations and challenges of current methods applied to apicomplexan noncoding RNA study and discuss future directions in this exciting field. The Emerging Importance of ncRNAs With little to no protein-coding capacity, noncoding RNA (ncRNA) (see Glossary) is an essential transcriptome component detected across all domains of life [1]. Although initially considered transcriptional noise (e.g., nonspecific or read-through transcription), ncRNAs have been shown to play critical roles in gene expression regulation at the levels of transcription, RNA processing, and translation [2]. Ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs) were first identified in the 1950s, followed by the discovery of small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) [2]. The first ncRNAs to be characterized were generally small (b300 nt except for rRNAs), contain stable secondary structure(s), and often operate as components of conserved RNA-protein complexes (Table 1). The ncRNA world blossomed in the early 2000s with advances in sequencing technologies. Since then, various long noncoding RNAs (lncRNAs), microRNA (miRNAs), and more recently tRNA-and snoRNA-derived small ncRNAs (18-40 nt) have been discovered [3,4]. ncRNAs are classified based on transcript length, secondary structure, and genomic and cellular localization [5] (Table 1). The abundance and variety of these molecules has reshaped our understanding of ncRNAs as fundamental transcriptional and post-transcriptional regulators. We emphasize lncRNAs in this review because this class of ncRNA is very heterogeneous and participates in an incredibly diverse set of processes. Most lncRNAs share many similarities with mRNAs, such as RNA polymerase II-mediated transcription, a 5′ 7-methylguanosine cap and a 3′ poly(A) tail [6]. Comparative analyses of lncRNAs reveal that they are not well conserved across species [7,8] and usually have greater tissue-or development-specific expression patterns than mRNAs [9]. By interacting with protein, DNA, or RNA molecules, lncRNAs participate in multiple layers of gene regulation including transcriptional, post-transcriptional, chromatin modification, and nuclear architecture conformation alterations (Box 1). The misregulation of lncRNAs in multicellular eukaryotes has been shown to lead to tumor genesis [10], cardiovascular disease [11], and ...

Full-Length Transcriptome Analysis of Plasmodium falciparum by Single-Molecule Long-Read Sequencing

“…Recently, it was revealed that non-coding RNAs play an important role in biological processes and gene function regulation in Apicomplexan parasites by experimental and sequencing technologies (Li et al, 2020). As for Plasmodium species, various strategies were carried out for non-coding RNA characterization (Mourier et al, 2008;Raabe et al, 2010;Liao et al, 2014;Siegel et al, 2014;Broadbent et al, 2015;Chappell et al, 2020).…”

The Modular Circuitry of Apicomplexan Cell Division Plasticity

“…For example, do we have the full library of epigenetic DNA and histone modifications, which both seem to have unique features in the Apicomplexa. Another big unknown is the role of (long) non-coding RNAs (Li et al, 2020) which are speculated to be key epigenetic regulators (Kim, 2018). Besides the wiring of the modules, many questions remain regarding the modules themselves.…”

“…3D chromosome organization is in general regulated by long noncoding RNA (lncRNA) molecules. Although non-coding RNA in Apicomplexa has not been extensively studied (Li et al, 2020), there is one validated example of this mechanism in Apicomplexa: regulation of P. falciparum gametocytogenesis is controlled by an antisense lncRNA transcribed from the gdv1 locus, which represses GDV1 (Filarsky et al, 2018). The role of GDV1 is to evict PfHP1 from histone 3 K9me3 sites to turn on gene expression and thereby committing to gametocytogenesis (Filarsky et al, 2018;Rea et al, 2018).…”

Cryptosporidium: Host-Parasite Interactions and Pathogenesis

“…There are clearly different gene expression profiles at asexual stage versus female gametocytes; and genes required for genetic recombination, amylopectin, trehalose metabolism and oocyst wall formation have been reported to be highly upregulated in the female gametocytes [37,41]. Recent studies have also reported the emerging role of long non-coding RNAs (lncRNA) delivered by Cryptosporidium into the host cell to manipulate host gene expression and pathogenesis [42][43][44][45].…”