The Emerging Field of Epitranscriptomics in Neurodevelopmental and Neuronal Disorders

Abstract

Analogous to DNA methylation and histone modifications, RNA modifications represent a novel layer of regulation of gene expression. The dynamic nature and increasing number of RNA modifications offer new possibilities to rapidly alter gene expression upon specific environmental changes. Recent lines of evidence indicate that modified RNA molecules and associated complexes regulating and "reading" RNA modifications play key roles in the nervous system of several organisms, controlling both, its development and function. Mutations in several human genes that modify transfer RNA (tRNA) have been linked to neurological disorders, in particular to intellectual disability. Loss of RNA modifications alters the stability of tRNA, resulting in reduced translation efficiency and generation of tRNA fragments, which can interfere with neuronal functions. Modifications present on messenger RNAs (mRNAs) also play important roles during brain development. They contribute to neuronal growth and regeneration as well as to the local regulation of synaptic functions. Hence, potential combinatorial effects of RNA modifications on different classes of RNA may represent a novel code to dynamically fine tune gene expression during brain function. Here we discuss the recent findings demonstrating the impact of modified RNAs on neuronal processes and disorders.

Keywords: Nm; RNA modification; disease; m5C; m6A; neurons; pseudouridine.

Figure 1

Some of the most common modifications in RNA.

Figure 2

RNA modifications are implicated in various neuronal processes. Distinct RNA modifications of tRNAs, small RNAs and mRNAs are required for common biological processes during brain development (left), neuronal differentiation (middle), and proper functioning of individual neuron (right), (see also Table 1). N6-methyladenosine (m⁶A), pseudouridine (Ψ), 5-methylcytosine (m⁵C), and 2′-O-methylation (Nm). The RNA classes in the brackets are the ones studied so far. Additional types with important functions may be modified as well.