The RNA Methylome Blackboard

Abstract

Articles, see p 518 and p 533 T he field of epigenetics focuses on the regulatory networks governing gene expression at a posttranscriptional and posttranslational level. The consequences of the dysregulation of these networks reverberate on intracellular signaling and on chromatin state, which in turn regulate gene expression. During the past decade, a considerable amount of knowledge has been generated on the understanding of how epigenetic events regulate cardiovascular development and their implication in the pathogenesis of cardiovascular diseases. Although the molecular and epigenetic mechanisms governing cardiac development, homeostasis, and disease are still not fully understood, significant progress has been made in elucidating the role of histones, the proteins around which DNA is wound, their acetylation and methylation, and also DNA and protein methylation. In aggregate, these studies have unveiled an intricate and dynamic multilayer network of regulation of enzymes and proteins with writer, reader, and eraser functions. 1,2 Whether RNA could be subject to epigenetic modifications remained a mystery for decades. Although there exists a myriad of chemical modifications that can be found on RNA, 3,4 RNA methylation (N 6-methyladenosine, m6A) is the most abundant modification in eukaryotic messenger RNAs, being present also in intronic regions of prespliced messenger RNA, transfer RNA, ribosomal RNA, and noncoding RNAs. 5 In the past several years, transcriptome-wide analyses of the m6A methylome in many species have revealed that this chemical modification is enriched in long ex-ons, near stop codons, and in the 3ʹ-untranslated regions of RNA. Similar to many histone and DNA modifications, RNA methylation is dynamic, mediated by writers (enzymes that add chemical modifications), readers (effector proteins that bind to modified macromolecules), and erasers (enzymes that delete chemical modifications), whose roles have been studied in many biological contexts. 5,6 Within the multiprotein complex responsible for the deposition of m6A marks, the methyltransferases-like 3 (METTL3) and METTL14, writers, and several other accessory proteins, as well, have been identified. 6 METTL3 knockout has been shown to be embryonically lethal, indicating a critical role for m6A during development. Conversely, m6A demethylases (erasers) contribute to the dynamic nature of the m6A mark, and, to date, only 2 such enzymes have been identified (FTO [fat mass and obesity-associated protein] and ALKBH5 [Alk homologue 5]). 7 Regardless of the recent remarkable progress in this field, the complex network of cellular events and signaling pathways contributing to the deposition of this chemical modification and the subsequent downstream control of gene expression in specific cell types, including cardiomyocytes, still remains largely unknown. Studying the epigenetic mechanisms controlling these processes will allow for better understanding of cardiac homeostasis and disease pathogenesis.