RNA methylation in nuclear pre‐mRNA processing

Abstract

Eukaryotic RNA can carry more than 100 different types of chemical modifications. Early studies have been focused on modifications of highly abundant RNA, such as ribosomal RNA and transfer RNA, but recent technical advances have made it possible to also study messenger RNA (mRNA). Subsequently, mRNA modifications, namely methylation, have emerged as key players in eukaryotic gene expression regulation. The most abundant and widely studied internal mRNA modification is N6‐methyladenosine (m6A), but the list of mRNA chemical modifications continues to grow as fast as interest in this field. Over the past decade, transcriptome‐wide studies combined with advanced biochemistry and the discovery of methylation writers, readers, and erasers revealed roles for mRNA methylation in the regulation of nearly every aspect of the mRNA life cycle and in diverse cellular, developmental, and disease processes. Although large parts of mRNA function are linked to its cytoplasmic stability and regulation of its translation, a number of studies have begun to provide evidence for methylation‐regulated nuclear processes. In this review, we summarize the recent advances in RNA methylation research and highlight how these new findings have contributed to our understanding of methylation‐dependent RNA processing in the nucleus.This article is categorized under: RNA Processing > RNA Editing and ModificationRNA Processing > Splicing Regulation/Alternative SplicingRNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

Glycogen synthase kinase‐3 and alternative splicing

“…GSK-3 also phosphorylates and destabilizes the RNA demethylase FTO (fat mass and obesity-associated protein); inhibition of GSK-3 causes accumulation of FTO which reduces overall levels of methylated (N 6 -methyladenosine or m 6 A) mRNAs (Faulds et al, 2018). In turn, m 6 A may regulate mRNA splicing, export, stability, or translation (Covelo-Molares, Bartosovic, & Vanacova, 2018).…”

mRNA Metabolism in Cardiac Development and Disease: Life After Transcription

“…Other than the above discussed 5′ capping and 3′ polyadenylation, recent studies have revealed a pervasive level of post-transcriptional modification in the mRNA transcriptome. In fact, more than 100 chemical moieties have been identified on the RNA molecules, and this undoubtedly contributes to an explosive increase in transcriptome complexity ( 43 , 63 , 161 , 170 , 182 , 200 ). This generally describes the area of research that aims to elucidate the role that transcriptional modifications play in transcript fate, and is now referred to as the field of epi-transcriptomics.…”

“…In general, m6A modification promotes mRNA translation and stability. Modification of these sites can influence many steps of mRNA metabolism, including CAP-independent translation, nuclear retention, alternative splicing, P-body targeting, translational modulation, and mRNA degradation ( FIGURE 7 ) ( 2 , 10 , 25 , 29 , 43 , 57 , 63 , 158 , 161 , 170 , 182 , 200 ). Despite a broad impact on mRNA metabolism, many of the molecular details involving m6A-dependent regulation of RNA remain unknown ( 29 ).…”

Epigenetic Signaling and RNA Regulation in Cardiovascular Diseases

“…The objective of this review is to explore epigenetic modifications particularly relevant to RNA biology with a particular focus on those crucial in cardiovascular physiology and pathophysiology. For a general description of the regulation and effects of epigenetic changes occurring at the RNA level, the reader is redirected to recent articles that are more detailed in mechanistic terms [4][5][6][7].…”