RNA modifications: emerging players in the regulation of reproduction and development

Abstract

The intricate world of RNA modifications, collectively termed the epitranscriptome, covers over 170 identified modifications and impacts RNA metabolism and, consequently, almost all biological processes. In this review, we focus on the regulatory roles and biological functions of a panel of dominant RNA modifications (including m6A, m5C, Ψ, ac4C, m1A, and m7G) on three RNA types—mRNA, tRNA, and rRNA—in mammalian development, particularly in the context of reproduction as well as embryonic development. We discuss in detail how those modifications, along with their regulatory proteins, affect RNA processing, structure, localization, stability, and translation efficiency. We also highlight the associations among dysfunctions in RNA modification-related proteins, abnormal modification deposition and various diseases, emphasizing the roles of RNA modifications in critical developmental processes such as stem cell self-renewal and cell fate transition. Elucidating the molecular mechanisms by which RNA modifications influence diverse developmental processes holds promise for developing innovative strategies to manage developmental disorders. Finally, we outline several unexplored areas in the field of RNA modification that warrant further investigation.

1. Introduction

RNA building blocks, i.e., A, U, C and G ribonucleotides, naturally undergo various chemical modifications. First reported in the 1950s [1–4], more than 170 modifications have been identified to date, and most types of RNA, if not all, have been observed with modifications [5]. These modifications, collectively known as the epitranscriptome, alter the inherent features of single nucleotides and greatly increase the information-encoding capacity of RNA.

RNA modification plays a central role in the regulation of RNA metabolism. The regulatory functions of modifications are best studied for three types of RNA that are indispensable for translation—transfer (tRNA), ribosomal (rRNA), and messenger RNA (mRNA). Modifications of these RNAs influence nearly all steps of RNA metabolism, such as RNA processing, RNA structure, cellular localization, stability, and translation efficiency, functioning as key connections between gene transcription and protein synthesis.

Using high-throughput sequencing methods, several RNA modifications, such as N6-methyladenosine (m6A) and 5-methylcytidine (m5C), have been mapped transcriptome-wide in various samples. With the development of low-input methods, the landscape of those RNA modifications has recently been revealed in rare cell populations, such as oocytes and early embryos. The spatiotemporal dynamics of RNA modifications across different biological contexts have significantly enriched our comprehension of their cellular roles. During development, cell fates are tightly regulated in each cell and coordinated within a cell population. In response to internal and/or external stimuli, cells make decisions to self-renew, proliferate or differentiate, which often requires prompt rewiring of the proteome before a new transcriptional profile can be fully established. RNA modifications, which are deposited in advance or swiftly altered in response to cues, may serve as a regulatory mechanism enabling rapid proteomic adaptation [6]. As this tight modulation of the proteome is pivotal for cell state transition, it is not surprising that dysfunction of RNA modification-related proteins (i.e., writers, erasers and readers) and abnormal deposition of RNA modifications have been linked to infertility [7–13], developmental disorders [14–16], and various diseases [17].