During differentiation, neurons exhibit a reorganization of DNA modification patterns across their genomes. The de novo DNA methyltransferase Dnmt3a is implicated in this process, but the effects of its absence have not been fully characterized in a purified neuronal population. To better understand how DNA modifications contribute to neuronal function, we performed a comprehensive analysis of the epigenetic and transcriptional landscapes of Dnmt3a-deficient mature olfactory sensory neurons (mOSNs), the primary sensory neurons of the olfactory epithelium. Dnmt3a is required for both 5-methylcytosine and 5-hydroxymethylcytosine patterning within accessible genomic regions, including hundreds of neurodevelopmental genes and neural enhancers. Loss of Dnmt3a results in the global disruption of gene expression via activation of silent genes and reduction of mOSN-expressed transcripts. Importantly, the DNA modification state and inducibility of odorant-activated genes are markedly impaired in Dnmt3a knockouts, suggesting a crucial role for this enzyme in establishing an epigenetic landscape compatible with neuronal plasticity.
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