Advances in brain epitranscriptomics research and translational opportunities

Abstract

Various chemical modifications of all RNA transcripts, or epitranscriptomics, have emerged as crucial regulators of RNA metabolism, attracting significant interest from both basic and clinical researchers due to their diverse functions in biological processes and immense clinical potential as highlighted by the recent profound success of RNA modifications in improving COVID-19 mRNA vaccines. Rapid accumulation of evidence underscores the critical involvement of various RNA modifications in governing normal neural development and brain functions as well as pathogenesis of brain disorders. Here we provide an overview of RNA modifications and recent advancements in epitranscriptomic studies utilizing animal models to elucidate important roles of RNA modifications in regulating mammalian neurogenesis, gliogenesis, synaptic formation, and brain function. Moreover, we emphasize the pivotal involvement of RNA modifications and their regulators in the pathogenesis of various human brain disorders, encompassing neurodevelopmental disorders, brain tumors, psychiatric and neurodegenerative disorders. Furthermore, we discuss potential translational opportunities afforded by RNA modifications in combatting brain disorders, including their use as biomarkers, in the development of drugs or gene therapies targeting epitranscriptomic pathways, and in applications for mRNA-based vaccines and therapies. We also address current limitations and challenges hindering the widespread clinical application of epitranscriptomic research, along with the improvements necessary for future progress.

Fig. 1. Epitranscriptome landscape.

Schematic illustration of several important RNA modifications focusing on mRNA, tRNA and rRNAs, as well as their writers, erasers, readers, and general molecular functions. The nucleus or cytoplasm localization of RNA modifications and their regulators are not specified. m⁶A: N⁶-methyladenosine; Ψ: Pseudo-uridine; m⁵C: C⁵-methylcytosine; m³C: N³-methylcytosine; m¹A: N¹-methyladenosine; m⁶Am: 2’-O-methyladenosine; m⁷G: N⁷-methylguanosine; m¹G: N1-methylguanosine; m²₂G: N2, N2 dimethylguanosine; τm⁵U: 5-taurinomethyluridine; τm⁵s²U: 5-taurinomethyl-2-thiouridine; f⁵C: 5-formylcytidine; i⁶A: N⁶-isopentenyladenosine; t⁶A: N⁶-threonylcarbamoyladenosine; Q: queuosinylation.

Fig. 2. Epitranscriptomics in the nervous system development.

Involvement of epitranscriptomics in regulating brain development, including embryonic neurogenesis (a), adult neurogenesis (b), gliogenesis (c), and synaptic transmission (d). Examples of brain development-related phenotypes in the mouse models with loss of function of several RNA modification regulators, like m⁶A, m⁵C, m³C, 2′-O-methylation, and A-to-I editing, are illustrated. A-to-I: A-to-I editing. LTP: Long-term potentiation.

Fig. 3. Functions of RNA modificaions in the adult nervous system.

Functions of RNA modifications in (a) learning and memory, (b) stress response, (c) neurodegeneration, (d) substance abuse disorders, (e) axon regeneration and brain injury, (f) post-ischemia recovery in the adult nervous system revealed by the gain- and loss-of-function experiments in mice and (g) in the adult human brain based on data from postmortem patient samples. TBI traumatic brain injury, CI-AMPAR calcium-impermeable AMPA receptor, CP-AMPAR calcium-permeable AMPA receptor; ↑↓: changes were observed in both directions depending on the brain region, environmental factors or specific transcripts.

Fig. 4. Alterations in RNA modification pathways associated with brain disorders in humans.

mcm⁵U: 5-methoxycarbonylmethyl uridine; mcm⁵s²U: 5-methoxycarbonylmethyl-2-thiouridine; ncm⁵U: 5-carbamoylmethyl uridine.

Fig. 5. Potential translational opportunities of epitranscriptomics in the nervous system.

a Application of epitranscriptomics as biomarkers for human brain disorders. The levels of RNA modifications, expression levels of RNA modification regulators, and mutations of RNA modification regulators can potentially be established as biomarkers for diagnostics or prognosis predictors of brain disorders, such as glioma (a1) or psychiatric disorders (a2). b Drugs and gene therapy for RNA modifications. Inhibitors of RNA modification regulators or CRISPR/Cas13-based RNA modification editing can be developed and used to manipulate the levels of RNA modifications and alleviate symptoms of brain disorders. For instance, FTO (the m⁶A eraser) and PUS7 (Ψ writer) inhibitors have the potential of attenuating the growth of GSCs (b1), and FTO inhibitors have the potential of restoring the cognitive deficits in AD and HD patients based on Fto KD and KO studies in mouse models (b2). c Mechanism-based downstream intervention. Deciphering dysregulated downstream molecular pathways mediating the pathogenesis of epitranscriptomics-related brain disorders can help to attenuate diseases by targeting and restoring specific dysregulated downstream molecular pathways or cellular processes. For example, impaired NPC maintenance caused by attenuated mitochondria activity in Mettl8 (mt-tRNA m³C writer) knockout mice can be rescued by pharmacologically enhancing mitochondria function with piracetam treatment (c1). d mRNA vaccines and mRNA therapy. Application of RNA modifications can enhance the protein expression and reduce the immunogenicity of mRNA introduced into the cells, potentially increasing the efficacy of mRNA vaccines (d1) and mRNA therapy (d2) targeting various brain disorders.