Regulation of the epigenome through RNA modifications

Abstract

Chemical modifications of nucleotides expand the complexity and functional properties of genomes and transcriptomes. A handful of modifications in DNA bases are part of the epigenome, wherein DNA methylation regulates chromatin structure, transcription, and co-transcriptional RNA processing. In contrast, more than 150 chemical modifications of RNA constitute the epitranscriptome. Ribonucleoside modifications comprise a diverse repertoire of chemical groups, including methylation, acetylation, deamination, isomerization, and oxidation. Such RNA modifications regulate all steps of RNA metabolism, including folding, processing, stability, transport, translation, and RNA's intermolecular interactions. Initially thought to influence all aspects of the post-transcriptional regulation of gene expression exclusively, recent findings uncovered a crosstalk between the epitranscriptome and the epigenome. In other words, RNA modifications feedback to the epigenome to transcriptionally regulate gene expression. The epitranscriptome achieves this feat by directly or indirectly affecting chromatin structure and nuclear organization. This review highlights how chemical modifications in chromatin-associated RNAs (caRNAs) and messenger RNAs (mRNAs) encoding factors involved in transcription, chromatin structure, histone modifications, and nuclear organization affect gene expression transcriptionally.

Keywords: Epigenome; Epitranscriptome; Gene expression; RNA modifications.

Figure 1.

Structure of canonical and modified nucleosides discussed in this Review.

Figure 2.

An integrated model of how RNA modifications influence the epigenetic regulation of gene expression. Chemical modifications of RNA can directly interfere with the intermolecular interactions of caRNAs, affecting their stability or capacity to recruit chromatin modifiers and transcriptional regulators. Modifications in ncRNAs directly affect their ability to form R-loops, their capacity to influence chromosome silencing, or their potential to form nuclear condensates such as the nucleolus, which is a powerhouse of ncRNA synthesis and modification. In addition, modifications in the mRNAs encoding chromatin modifiers or transcriptional regulators indirectly feedback to control gene expression transcriptionally.

Figure 3.

Role of m⁶A in transcriptional regulation of gene expression. A. m⁶A induces the degradation of caRNAs leading to a closed chromatin state. B. m⁶A induces degradation of IAP-RNAs while recruiting chromatin modifiers that promote heterochromatin formation around IAPs. C. m⁶A promotes H3K9 demethylation via recruiting the lysine demethylase KDM3B. D. m⁶A promotes DNA demethylation via recruiting TET1.