Chemical Modulation of RNA Epigenetic Modifications

Given the increasing evidence demonstrating the notable functions of RNA modifications, the precise regulation of a particular epigenetic mark is high desirable. Current genetic techniques like over-expression or knockout of corresponding genes/proteins, as well as the development of molecular inhibitors/antagonists of these enzymes facilitated a prompt epigenetic associated phenotype observation. However, these approaches heavily relied on the characterization of RNA modifying enzymes. In vitro or in vivo alteration of RNA epigenetics, especially for those modifications whose pathways have not been identified, through direct chemical interventions with small organic molecules would fulfill this gap and is thus highly desirable. Considering the fact that those enzymatic modifications and de-modifications are chemical reactions occurred in the homeostasis constraints of a living system, we believe it would be possible for developing the corresponding their biomimetic counterparts. In this Review, we will present our recent advances regarding the direct chemical interventions towards several biologically important RNA modifications and their applications in live cells or growing plants. We have demonstrated that the demethylation process of N⁶-methyladenosine m⁶A in live cells could be accomplished through Flavin mononucleotide prompted biocompatible photo-oxidation. This is the first example of small organic molecules modulating in vitro RNA epigenetic modifications. We also presented a straightforward transformation for the generation of 5-formylcytidine f⁵C from 5-methylcytidine m⁵C using anthraquinone-2-sulfonate without oxidizing other biomacromolecules or redundancy production of 5-hydroxymethylcytidine hm⁵C. Most recently, we reported that oxoammonium cations might be applied as artificial deprenylases for the highly sensitive and selective demodification of N⁶-prenyladenosine i⁶A in oligonucleotides, cells and even live plants. One of the most striking features of these “artificial enzymes” is their low cytotoxic activity on cells and extraordinary capability in regulating designated modifications without over-expression or inhibiting corresponding enzymes or disturbing other epigenetics, nucleic acids, or proteins. The objective of this Review is to present the research findings regarding the design, synthesis and evaluation of highly efficient chemical reagents and biocompatible transformations toward selected RNA epigenetics that have enabled chemists’ ability to not just controlling in vitro/in vivo RNA modifications, but also introducing artificial variants onto natural RNAs, without disturbing any related enzymes. Such double direction regulating may considerably help in the function interpretation/installation/modulation of versatile modifications pertaining to RNAs. The ability of those chemical motifs will undoubtedly illuminate undisclosed functions and regulatory mechanisms affiliated to the vast majority of discovered modifications and has the potential to enable treatments for related human diseases.