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Epitranscriptomics: History
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Subjects: Genetics & Heredity
Contributor: Shizuka Uchida

Epitranscriptomics means the field of RNA modifications, which has been extended to other RNA molecules, including protein-coding genes, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). 

  • epitranscriptomics
  • non-coding RNA
  • RNA modifications

1. Introduction

Just as DNA and proteins, RNA can be modified by a variety of enzymes. There are 170+ RNA modifications known to date [1][2], which is much higher than DNA and proteins. Historically, RNA modifications have been studied for those of housekeeping RNAs, such as ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs) [3][4][5][6][7] and only recently that the field of RNA modifications (called epitranscriptomics [8]) has been extended to other RNA molecules, including protein-coding genes, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). This expansion of the epitranscriptomic field is the result of the recent development of high-throughput methods, such as mass spectrometry and next-generation sequencing (NGS), especially RNA sequencing (RNA-seq) [9][10][11][12][13]. Among many RNA modifications, the most famous one in recent years is N6-methyladenosine (m6A), which is reversible methylation of nitrogen-6 position of adenosine (A) [14][15]. This modification frequently occurs in most eukaryotes, especially in the messenger RNAs (mRNAs) [16][17][18][19] and has been shown to increase during organ maturation and development [20][21][22][23] especially in the adult brain [24], cancer pathogenesis, and progression [25][26]. Because of increased interest in epitrascriptomics, there is an explosion in the number of publications covering various aspects of cellular processes, organ developments, and disease progressions for many different RNA modifications, including m6A, RNA editing, and pseudouridylation. These RNA modifications have contributed significantly to RNA metabolism, including transcription, splicing, subcellular location, stability, and translation.

2. Impact of Epitranscriptomic Marks on lncRNA Structures

When the first draft of the human genome was introduced, there were high hopes for understanding many of nature’s rules about the human body. Two decades later, we have realized that there is more to human genes than simply looking at DNA sequences. The same situation applies to elucidating the functions of lncRNAs. Many researchers were excited to read about terminal differentiation-induced non-coding RNA (TINCR) as the authors identified TINCR box motifs, which are 25-nt long RNA sequences that interact with many other mRNAs [27]. The discovery of TINCR box motifs prompted a further search for similar binding domains of other lncRNAs. However, such screening did not yield fruitful results [28][29]. Not only was such search not successful, but it also recently became clear that TINCR owns an evolutionary conserved open reading frame, which encodes for peptides of 87 amino acids [30]. Within this TINCR peptide, one of 10 TINCR box motifs is included, suggesting that sequence alone cannot be used to infer functions of lncRNAs. There are a number of methods proposed and used to predict the functions of lncRNAs by combining different features of lncRNAs, including evolutionary-conserved sequence motifs, secondary structures, and potential binding of RNA-binding proteins and miRNAs [28][29][31][32]. Yet, none of such methods can predict the functions of all lncRNAs, which is not surprising as not all protein-coding genes have been functionally characterized. In addition to the current challenges facing the computational functional predictions of lncRNAs, growing evidence of epitranscriptomic marks on lncRNAs is of particular interest as yet another parameter that researchers need to consider when investigating the functions of lncRNAs and other types of RNA species.
More than half of the human genome is made up of repetitive sequences [33]. The Ensembl database currently classifies these repeat sequences into 10 classes (centromere, low complexity regions, RNA repeats, satellite repeats, simple repeats, tandem repeats, LTRs (long tandem repeats), SINE (short interspersed nuclear element), LINE (long interspersed nuclear element), and Type II transposons) and categorize those that cannot be classified into above 10 classes as “Unknown” (https://m.ensembl.org/info/genome/genebuild/assembly_repeats.html accessed on 22 March 2021). Not surprisingly, such repetitive sequences are also present in lncRNAs [34][35][36]. For example, the subfamily of SINE, Alu elements, can be found in 11% of the human genome [37]. These 300-nt repetitive repeats are derived from transposons and exist only in primates. These elements can be expressed as their own RNA [38] or parts of other transcripts (e.g., introns of mRNAs, lncRNAs), where their expression levels increase upon stresses (e.g., heat shock, hypoxia, viral infection) [39][40]. When two Alu elements in opposite directions meet, they form double-stranded RNA, which can be recognized by RNA-binding proteins, such as ADARs. The ADAR-mediated A-to-I changes also occur frequently in lncRNAs [41][42][43]. Not surprisingly, these A-to-I conversions change the secondary structures of RNA [44], which is also an important point to be considered when analyzing for lncRNA functions as the binding of other macromolecules (i.e., DNA, RNA, and proteins) can alter depending on the presence (or absence) of double-stranded RNA motifs within a lncRNA [45][46][47].
Besides A-to-I RNA editing, other epitranscriptomic marks affect the structures of lncRNAs. In particular, m6A marks are of interest as it has been shown to be in a negative relationship with A-to-I RNA editing [48]. More recently study shows that silencing of the m6A writer, METTL3, in glioma stem-like cells altered A-to-I and C-to-U RNA editing (another type of RNA editing, which is less frequent than A-to-I) events by differentially regulating RNA editing enzymes ADAR and APOBEC3A, respectively [49]. An interesting model is proposed recently regarding m6A marks affecting the secondary structure of one of the most well studied lncRNA, MALAT1 [50]. By performing secondary data analyses of dimethyl sulfate-sequencing (DMS-Seq) data from human erythroleukemic cell line K562 and psoralen analysis of RNA interactions and structure (PARIS) data from cervical cancer-derived HeLa cells compared to the working structural model of MALAT1 in noncancerous cells, the authors postulated that m6A-based structural changes of MALAT1 might mediate cancer in a cell-type-specific manner [50]. Thus, increasing evidence suggests that examining epitranscriptomic marks on lncRNAs is important to uncover the potential functions of lncRNAs [51].

3. Conclusions

On the whole, we summarize updates on lncRNA epitranscriptomics, in the context of lncRNA function and biology. Even though the last couple of decades of research revealed the importance of epitranscriptomics in health and disease, several questions still need to be answered, such as future insights into the functional importance of RNA modification in lncRNAs? Are these modifications conserved between species, whether these modifications are mediators or actual drivers? How do we identify different modifications on the same lncRNA? Can these modifications be targeted to restrict disease progression? All these above questions would unravel our understanding of epitranscriptomics as novel disease mechanisms to design effective and targeted therapeutics.

This entry is adapted from the peer-reviewed paper 10.3390/ncrna7020031

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