RNA methylation in neurodevelopment and related diseases

Abstract

Biological development and genetic information transfer are governed by genetic, epigenetic, transcriptional, and posttranscriptional mechanisms. RNA methylation, the attachment of methyl (–CH3) groups to RNA molecules, is a posttranscriptional modification that has gained increasing attention in recent years because of its role in RNA epitranscriptomics. RNA modifications (RMs) influence various aspects of RNA metabolism and are involved in the regulation of diverse biological processes and diseases. Neural cell types emerge at specific stages of brain development, and recent studies have revealed that neurodevelopment, aging, and disease are tightly linked to transcriptome dysregulation. In this review, we discuss the roles of N6-methyladenine (m6A) and 5-methylcytidine (m5C) RNA modifications in neurodevelopment, physiological functions, and related diseases.

1. Introduction

Diverse and dynamic gene regulation by RNA modifications is critical for defining cellular function and phenotype. Among the more than 170 different chemical modifications in eukaryotic cells, the ones that have been intensively researched in the epitranscriptome are N6-methyladenosine (m6A), N6,2′-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 5-hydroxymethylcytosine (hm5C), and pseudouridine (ψ) [1]. These RNA modifications impact RNA metabolism by regulating RNA processing events such as alternative splicing, transportation, stability, translation, and miRNA processing [2–4]. Recent advancements in high-throughput sequencing technologies have enabled transcriptome-wide mapping of these modifications, revealing their pervasive and dynamic presence across different biological situations.

The central nervous system (CNS), which includes the brain and spinal cord, is the primary control center for coordinating information processing and responses in organisms. The formation and function of the CNS are regulated by a myriad of factors, among which RNA modifications have emerged as major contributors [5,6]. m6A is the most prevalent RNA modification in the mammalian transcriptome [7]. It has several effects on the nervous system, including self-renewal of neural stem cells, cognitive processes such as learning and memory, maturation of neurons, expansion of synaptic connections, and proliferation of glioma cells [8,9]. m5C modifications are particularly common in brain tissues and play a significant role in the CNS [10]. For example, m5C in neurons has been associated with the cellular stress response and programmed cell death [11]. This study revealed a strong correlation between m5C modifications and both brain angiogenesis and nervous system development in zebrafish brains exposed to hypoxic circumstances [1].

These findings indicate that both m5C and m6A modifications play significant roles in brain development and function, as well as in the initiation of neurological diseases. However, for a more comprehensive understanding of these relationships and their potential therapeutic applications, additional research is needed. This review aims to provide a thorough and extensive summary of our current understanding of RNA modifications, with a specific focus on m6A and m5C. We focus on their distribution, regulation, and functional roles in mammalian neurodevelopment, physiology, and disease. Additionally, we address the challenges faced in the study of RNA modifications and consider potential future paths in this field.