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Autism Spectrum Disorder (ASD), a complex neurodevelopmental condition, is characterised by reduced social and emotional expression and repetitive patterns of behaviour. The clinical observations of defects in brain development and disrupted connectivity in ASD correlate with the perturbations at the neuronal and molecular levels. While the underlying genetic basis has been extensively studied, understanding the epigenetic and epitranscriptomic regulation has only begun to unravel in the past two decades. This work aims to link the ASD clinical phenotypes to the molecular dysfunction, specifically highlighting one of the crucial mRNA modifications, N6-methyladenosine (m 6 A). During neuronal development, m 6 A, a key post-transcriptional regulator, dynamically modulates mRNA translation at synapses and is essential for maintaining synaptic plasticity. However, the mechanisms by which m 6 A operates at synapses in the context of ASD are poorly understood. Our work establishes connections across neuronal developmental timelines to m 6 A regulation and discusses the possibility of how this dysregulation may underlie the development of synaptopathies observed in ASD. By integrating previously published m 6 A-seq and CLIP-seq data with the SFARI gene database, we found that 41.59% (515 of 1,238 genes) of ASD risk genes are m 6 A-enriched. Specifically, we found 28 syndromic genes overlapping with the Synaptic m 6 A Epitranscriptome (SME). Here, we also shed light on the importance of m 6 A readers, with a focus on FMRP and YTHDF1 and their regulation at the synapse. Altogether, we suggest a model in which m 6 A-mediated post-transcriptional regulation influences ASD-related synaptic dysfunction.
Doijad et al. (Fri,) studied this question.