The Regulation of RNA Modification Systems: The Next Frontier in Epitranscriptomics?

Abstract

RNA modifications, long considered to be molecular curiosities embellishing just abundant and non-coding RNAs, have now moved into the focus of both academic and applied research. Dedicated research efforts (epitranscriptomics) aim at deciphering the underlying principles by determining RNA modification landscapes and investigating the molecular mechanisms that establish, interpret and modulate the information potential of RNA beyond the combination of four canonical nucleotides. This has resulted in mapping various epitranscriptomes at high resolution and in cataloguing the effects caused by aberrant RNA modification circuitry. While the scope of the obtained insights has been complex and exciting, most of current epitranscriptomics appears to be stuck in the process of producing data, with very few efforts to disentangle cause from consequence when studying a specific RNA modification system. This article discusses various knowledge gaps in this field with the aim to raise one specific question: how are the enzymes regulated that dynamically install and modify RNA modifications? Furthermore, various technologies will be highlighted whose development and use might allow identifying specific and context-dependent regulators of epitranscriptomic mechanisms. Given the complexity of individual epitranscriptomes, determining their regulatory principles will become crucially important, especially when aiming at modifying specific aspects of an epitranscriptome both for experimental and, potentially, therapeutic purposes.

From RNA World to SARS-CoV-2: The Edited Story of RNA Viral Evolution

“…These lesions can result in RNA breakage or can block RNA, where the broken RNA genomes would be either lost or participate in recombination like events which can in turn produce rearranged genomes (see Section 3 and Figure 2 ). Like DNA, RNA base lesions and modifications can be caused by a variety of endogenous and exogenous agents ( Table 1 and [ 31 , 32 , 96 , 97 , 98 , 99 , 100 , 101 ]). However, unlike for DNA, most base lesions in RNA cannot be repaired.…”

“…There have been 170 different RNA modifications identified in RNA across all species, with 60 of those being identified in eukaryotes [ 107 ]. Many of these RNA modifications have multiple functional consequences [ 99 , 108 , 109 ] and altogether are referred as the RNA-editome, or as the epitranscriptome. Investigations into the RNA modifications in viruses are still in its infancy, but even so, several enzymatic modifications of viral RNA bases have been reported ( Table 1 [ 31 , 32 , 96 , 97 , 98 , 99 , 100 , 101 ]).…”

“… Table 1 contains a summary of information compiled from [ 31 , 32 , 96 , 97 , 98 , 99 , 100 , 101 , 105 , 106 ]. …”

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

“…At cellular and molecular levels, these modifications have been suggested to have varying degrees of dynamics relative to the RNA transcript in which they reside. [ 159 , 160 , 161 , 162 , 163 , 164 ]. Moreover, several sites in a single transcript can be targeted for modification.…”

Gene Signature And Prognostic Values of m5C-Related Regulators In Colon Adenocarcinoma

“…Traditional epigenetic modi cations, including chromatin remodeling, DNA methylation, and histone modi cations, are involved in various biological processes related to the occurrence and progression of tumors, including gastrointestinal cancers [2][3][4]. With considerable progress in zymology and high-throughput sequencing technology, epitranscriptomics has attracted signi cant attention recently [5][6][7][8][9][10]. Research investigating the physiological and pathological functions of RNA modi cations have identi ed multiple dynamic modi cations of RNA, including N6-methyladenosine (m 6 A), 2-O-dimethyladenosine (m 6 Am), 5-methylcytosine (m 5 C), 7methylguanosine (m 7 G), N1-methyladenosine (m 1 A), and pseudouridylation (Ψ) [11,12].…”