Mechanisms of epitranscriptomic gene regulation

Abstract

Chemical modifications on RNA can regulate fundamental biological processes. Recent efforts have illuminated the chemical diversity of posttranscriptional ("epitranscriptomic") modifications on eukaryotic messenger RNA and have begun to elucidate their biological roles. In this review, we discuss our current molecular understanding of epitranscriptomic RNA modifications and their effects on gene expression. In particular, we highlight the role of modifications in mediating RNA-protein interactions, RNA structure, and RNA-RNA base pairing, and how these macromolecular interactions control biological processes in the cell.

Figure 1.

Chemical structures of known epitranscriptomic mRNA modifications.

Figure 2.

Protein readers of epitranscriptomic modifications. Different reader proteins bind to m⁶A, m⁵C, and m¹A and regulate cellular fate of modified RNAs.

Figure 3.

Anti-readers of m⁶A and m⁵C. RNA-binding of G3BP1 and SRSF2 is significantly reduced with m⁶A- and m⁵C-modified RNAs, respectively.

Figure 4.

Structural and translational effects of RNA modifications. A) m⁶A-switch: m⁶A destabilizes RNA duplex and exposes the opposite strand that is a binding target for HNRNPC/G. B) m⁶A in CDS can impede translation but can recruit YTHDC2 to increase translational rate in structured regions. C) Pseudouridine can recode mRNAs during translation. D) N⁴-acetylcytidine in CDS increases translation elongation.