THE ROLE OF RNA M6A-EPITRANSCRIPTOMIC IN NEURONAL HOMEOSTATIC PLASTICITY

The RNA modification via N⁶-methyladenosine (m⁶A) regulates the gene expression landscape and is implicated in multiple cellular and physiological processes. Given the emerging role of m6A in brain function and dysfunction, here, we investigated the functional importance of the m6A-RNA-transcriptome in homeostatic plasticity. Chronic inactivation in neurons is known to induce homeostatic upscaling response, an important mechanism in stabilising neuronal circuitry. By knocking down the m6A-methyltransferase enzyme, Mettl3, in primary cortical neurons, we observed significant impairment in homeostatic upscaling response. Transcriptome-wide analysis of m6A revealed a large subset of transcripts differentially methylated in response to neuronal inactivity, which positively correlate with the changes in their transcript levels. As the functional consequences of m6A on the target mRNAs are largely mediated by the m6A-readers, we examined the regulation of these proteins, namely YTHDF1 and FMRP, which have been associated with neuronal plasticity. Chronic inactivation enhanced the interaction of YTHDF1 and FMRP in neurons, but this is significantly perturbed in Mettl3 knockdown neurons. In our working model, we propose that in response to chronic inactivation, m6A provides a critical RNA regulatory layer in conjunction with transcriptional changes that occur to elicit the homeostatic mechanism in neurons.