An exciting time for epitranscriptomics

Epigenetics is a well-established means of gene regulatory control where chemical modifications of DNA bases or their associated histone proteins affect the expression of genes (as opposed to DNA sequence). These epigenetic marks may take the form of methylation (usually on cytosine residues) or histone acetylation/phosphorylation/ubiquitination/sumoylation etc. and can be passed down to daughter cells. Epigenetic changes are induced by the environment and provide a biological mechanism by which nurture as opposed to nature, plays a significant role in shaping our behaviours and characteristics.

Recently, scientists are uncovering the functional significance of epitranscriptomics – or the chemical modification of RNA. The first report of mRNA modification, specifically,  methylation of the N6 position of adenosine (m6A), occurred in 1974 by Fritz Rottman et al.. The m6A modification is the most common eukaryotic mRNA modification however its functional significance remained unclear until the 2010s. In 2012, Dominissini et al. using m6A-antibody enriched RNA-seq, discovered 12000 methylated sites in 7000 coding genes and 250 non-coding genes. Typically highly concentrated around stop codons, within long internal exons and at transcription start sites, it became evident that genes without these modifications tend to be more highly expressed. He writes about it in a Science essay here.

There are several players involved in epitranscriptomics, and they are often referred to as writers, readers and erasers. A methyltransferase METTL3 (“writer“) produces the m6A modification, the YT521-B homology (YTH) domain family of proteins are “readers” that bind to m6A modified RNA and regulate functions that affect protein expression such as RNA degradation, translation and splicing. Finally the “erasers” such as enzyme FTO, implicated in various diseases such as cancer and obesity, removed these m6A marks. Thereby completing the set of actors required for establishing epitranscriptomics as a regulatory mechanism for RNA expression.

Samie Jaffery’s group recently published a controversial paper that identified another epitranscriptomic modification N6,2O-dimethyladenosine (m6Am), located near the 5′ caps of mRNA, that is the main substrate of eraser FTO instead of m6A. m6Am is correlated with increased mRNA stability as it makes 5′ caps harder to remove, which thereby increases protein expression. This is in contrast with m6A modification, which is associated with suppression of protein expression. This highlights distinct functional roles of these RNA methylation marks.

There are already studies demonstrating m6A regulation is utilized also by non-coding RNA. The simple self-made schema below shows how m6A modification was used by Xist to carry out its transcriptional repression of the X chromosome, demonstrated by Patil et al. in a recent Nature publication.

xistm6a

Epitranscriptomics is a relatively young field and opens up new possibilities to study how RNAs are regulated and in particular, how non-coding RNAs may carry out their functions. This signals yet more exciting times ahead for RNA researchers!

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