Abstract
In the past few years, thorough investigation of chemical modifications operated in the cells on ribonucleic acid (RNA) molecules is gaining momentum. This new field of research has been dubbed “epitranscriptomics”, in analogy to best-known epigenomics, to stress the potential of ensembles of RNA modifications to constitute a post-transcriptional regulatory layer of gene expression orchestrated by writer, reader, and eraser RNA-binding proteins (RBPs). In fact, epitranscriptomics aims at identifying and characterizing all functionally relevant changes involving both non-substitutional chemical modifications and editing events made to the transcriptome. Indeed, several types of RNA modifications that impact gene expression have been reported so far in different species of cellular RNAs, including ribosomal RNAs, transfer RNAs, small nuclear RNAs, messenger RNAs, and long non-coding RNAs. Supporting functional relevance of this largely unknown regulatory mechanism, several human diseases have been associated directly to RNA modifications or to RBPs that may play as effectors of epitranscriptomic marks. However, an exhaustive epitranscriptome’s characterization, aimed to systematically classify all RNA modifications and clarify rules, actors, and outcomes of this promising regulatory code, is currently not available, mainly hampered by lack of suitable detecting technologies. This is an unfortunate limitation that, thanks to an unprecedented pace of technological advancements especially in the sequencing technology field, is likely to be overcome soon. Here, we review the current knowledge on epitranscriptomic marks and propose a categorization method based on the reference ribonucleotide and its rounds of modifications (“stages”) until reaching the given modified form. We believe that this classification scheme can be useful to coherently organize the expanding number of discovered RNA modifications.
Highlights
Pseudouridine (C5-glycoside isomer of uridine), the first post-transcriptional ribonucleic acid (RNA) modification identified, was discovered in 1957 [1], but, only decades later, the term “epitranscriptomics” was created to describe how that and many other modifications are not genetically encoded but, rather, added on top— the prefix “epi” taken from the Greek that means “on top of”—of the transcribed nucleotides [2]
We already know that RNA modification and editing events are involved in maintaining the functionality of many living systems by impacting on many essential RNA-processing events, such as splicing, transport, localization, translation, and stability, research on functions and mechanisms acted by the epitranscriptome is still in an early phase
We cannot rule out different biological roles even for the same RNA modification occurring at the same site in different species
Summary
Pseudouridine (C5-glycoside isomer of uridine), the first post-transcriptional ribonucleic acid (RNA) modification identified, was discovered in 1957 [1], but, only decades later, the term “epitranscriptomics” was created to describe how that and many other modifications are not genetically encoded but, rather, added on top— the prefix “epi” taken from the Greek that means “on top of”—of the transcribed nucleotides [2]. Experimental protocols for selective chemical modification and identification of modified residues are available for dihydrouridine (D), I, m5C, m7G, 2’-O-methylation (Nm), and Ψ [25] These detection methods have provided valuable information in the last years, they can be used to investigate only a minority of epitranscriptomic marks because of the limited. Availability of antibodies (likely due to the small size of the antigen, the modified ribonucleoside) and the lack of chemical compounds selectively reactive towards a particular RNA modification (an updated overview of the sequencing methods for RNA modification mapping is provided in Reference [25]) These methods often require complex and time-consuming protocols and still have some limitations (mainly caused by RNA fragmentation) with respect to specific isoform detection, information about strand-specificity, and occurrence of multiple methylation sites along the same transcript [26]. We present a census of currently known RNA modifications, along with a proposed method for classifying these epitranscriptomic marks based on the natural ribonucleotide subject of the modification process and the number of steps occurred until reaching the final output
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