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.