Abstract
The intrinsic cellular heterogeneity and molecular complexity of the mammalian nervous system relies substantially on the dynamic nature and spatiotemporal patterning of gene expression. These features of gene expression are achieved in part through mechanisms involving various epigenetic processes such as DNA methylation, post-translational histone modifications, and non-coding RNA activity, amongst others. In concert, another regulatory layer by which RNA bases and sugar residues are chemically modified enhances neuronal transcriptome complexity. Similar RNA modifications in other systems collectively constitute the cellular epitranscriptome that integrates and impacts various physiological processes. The epitranscriptome is dynamic and is reshaped constantly to regulate vital processes such as development, differentiation and stress responses. Perturbations of the epitranscriptome can lead to various pathogenic conditions, including cancer, cardiovascular abnormalities and neurological diseases. Recent advances in next-generation sequencing technologies have enabled us to identify and locate modified bases/sugars on different RNA species. These RNA modifications modulate the stability, transport and, most importantly, translation of RNA. In this review, we discuss the formation and functions of some frequently observed RNA modifications—including methylations of adenine and cytosine bases, and isomerization of uridine to pseudouridine—at various layers of RNA metabolism, together with their contributions to abnormal physiological conditions that can lead to various neurodevelopmental and neurological disorders.
Highlights
RNA is subjected to multifaceted regulatory processes to sustain diversity and complexity at the organismal and molecular levels
Precise spatial and temporal expression of various proteins is essential for appropriate brain development, which is achieved by proper accomplishment of RNA stabilization, transport and translation [4]
Different aspects of RNA metabolism contribute to neurodegenerative diseases and neurodevelopmental disorders, RNA-binding proteins (RBPs) play important roles in both kinds of disease pathogenesis [2,5]
Summary
RNA is subjected to multifaceted regulatory processes to sustain diversity and complexity at the organismal and molecular levels. The functional impact of the epitranscriptome manifests in almost all tissues, but it is most apparent in regulating complex organs such as the brain It is both transcriptomic and epitranscriptomic diversity that endows the nervous system with its complexity, with the latter altering various layers of RNA metabolism. RNA metabolism encompasses diverse processes including biogenesis, transport, splicing, stabilization, storage, and translation. RNA modifications at the single nucleotide level, which can be linked to mechanisms underlying tissue-specific and age-dependent gene expression profiles or to the pathophysiology of complex diseases such as cancer [5]. Three groups of protein factors—known as “writers”, “readers” and “erasers”—are involved in drafting the epitranscriptome, with writers and erasers possessing substrate-specific enzymatic activities Together, these are known as RNA-modifying proteins (RMPs). RNA modifications on various aspects of RNA metabolism and evaluate links between those modifications and a variety of neurological diseases
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