2. THE EPITRANSCRIPTOME versus THE EPIGENOME.
Today, a lot of expectation rests on whether the novel field of epitranscriptomics will follow the exploitation plan reached by epigenetics in drug development. To perform a critical overview, we need to identify common and divergent features between epigenetic and epitranscriptome modifications. Both RNA and DNA modifications share common features, including their reversibility and dynamisms determined by a set of proteins with writer, reader, or eraser function, and these proteins react to changing external conditions (Fu et al., 2014; Dominissini et al., 2016; Roundtree and He, 2016). Regrettably, we still do not have a full picture of the extent of RNA modifications and associated enzymatic machinery, but a general overview could be anticipated. So far, it is known that the number of RNA modifications is high, which involves a considerable number of writers, erasers and readers. These enzymes are potential pharmacological targets guided to modify their catalytic activity or their target binding-sites. In addition, RNA modifications, such as epigenetic modifications, are established in a cell type and time-dependent manner.
Major differences included the following aspects: (i) in contrast with the primary role of DNA modifications as regulators of gene transcription, all type of RNA modifications can be associated with wider aspects of gene expression, including splicing, distribution, translation and stability. The function seems to be strongly dependent on the specification of the RNA-specie. The same RNA modification can be recognized by multiple readers in a context- dependent manner resulting in different mechanisms of action and affecting variable biological pathways (Jia et al., 2011; Wang et al., 2014). (ii) RNAs demonstrate mobility between cellular compartments, a characteristic that amplifies their effects on multiple biological pathways.(iii) The heritability: whilst epigenetic modifications show mitotic inheritance, so far, a transmission of RNA modifications have not been described. When RNA degradation occurs, the epitranscriptomic mark is lost. (iv ) The structural effect: whilst DNA methylation does not alter the double helix DNA structure, RNA modifications could result in altered charge, base-pairing potential, secondary structure, and protein- RNA interactions (Liu et al., 2015). This conformational change also influence how the modification works functionally, since changes in RNA modifications could be read directly by their targets but also indirectly though the effect on their structural change.
All together, we can assume that the “RNA word” is tremendously complex and the current level of knowledge is still somewhat limited. In next sections, we will introduce the major research scenarios for making RNA-modifications an actionable target in drug discovery.