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.

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

“…There are over 100 types of tRNA modifications that range from simple methylation to complex modifications involving multiple chemical groups (El Yacoubi, Bailly, & de Crecy‐Lagard, 2012; Ontiveros, Stoute, & Liu, 2019). Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al, 2018; Ramos & Fu, 2019). In particular, the brain appears to be sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification enzymes such as: the Elongator complex (Hawer et al, 2018; Kojic & Wainwright, 2016); ADAT3 (Alazami et al, 2013; El‐Hattab et al, 2016; Ramos, Han, et al, 2019); NSUN2 (Abbasi‐Moheb et al, 2012; Khan et al, 2012; Martinez et al, 2012); FTSJ1 (Dai et al, 2008; Freude et al, 2004; Froyen et al, 2007; Gong et al, 2008; Guy et al, 2015; Ramser et al, 2004; Takano et al, 2008); WDR4 (Chen et al, 2018; Shaheen et al, 2015; Trimouille et al, 2018); KEOPS complex (Braun et al, 2017); PUS3 (Abdelrahman, Al‐Shamsi, Ali, & Al‐Gazali, 2018; Shaheen, Han, et al, 2016); CTU2 (Shaheen, Al‐Salam, El‐Hattab, & Alkuraya, 2016; Shaheen, Mark, et al, 2019); TRMT10A (Gillis et al, 2014; Igoillo‐Esteve et al, 2013; Narayanan et al, 2015; Yew, McCreight, Colclough, Ellard, & Pearson, 2016; Zung et al, 2015); PUS7 (de Brouwer et al, 2018; Shaheen, Tasak, et al, 2019); and ALKBH8 (Monies, Vagbo, Al‐Owain, Alhomaidi, & Alkuraya, 2019).…”

The m6A reader Ythdf restricts axonal growth inDrosophilathrough target selection modulation of the Fragile X mental retardation protein

“…Increasing evidence suggests a central role of m 6 A during nervous system development and functions (Angelova et al, 2018;Du et al, 2019;Jung and Goldman, 2018;Li et al, 2019;Livneh et al, 2020;Widagdo and Anggono, 2018). m 6 A is present at particularly high levels in the nervous system of different model animals (Lence et al, 2016;Meyer et al, 2012), and these levels can vary following behavioral stimuli or sensory experience (Engel et al, 2018;Koranda et al, 2018;Widagdo et al, 2016;Yoon et al, 2018).…”

A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability

“…There are over 100 types of tRNA modifications that range from simple methylation to complex modifications involving multiple chemical groups (El Yacoubi et al 2012;Ontiveros et al 2019). Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al 2018;Ramos and Fu 2018). In particular, the brain appears to be exquisitely sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification (Abbasi-Moheb et al 2012;Alazami et al 2013;Blanco et al 2014;de Brouwer et al 2018;El-Hattab et al 2016;Khan et al 2012;Komara et al 2015;Martinez et al 2012;Monies et al 2019;Ramos et al 2019;Shaheen et al 2015;Shaheen et al 2016a;Shaheen et al 2016b;Shaheen et al 2019a;Shaheen et al 2019b).…”