PT - JOURNAL ARTICLE AU - Mohan C Manjegowda AU - Jonathan Joy-Gaba AU - Eric Wengert AU - Anusha U. Saga AU - Daniel Warthen AU - Amelie Kuchler AU - Ronald Gaykema AU - Manoj K. Patel AU - Nathan C. Sheffield AU - Michael M. Scott TI - DNA Methyltransferase 1 and 3a Expression in the Frontal Cortex Regulates Palatable Food Consumption AID - 10.1101/2021.05.23.445176 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.05.23.445176 4099 - http://biorxiv.org/content/early/2021/05/23/2021.05.23.445176.short 4100 - http://biorxiv.org/content/early/2021/05/23/2021.05.23.445176.full AB - DNA methylation is an important regulatory mechanism in the control of neuronal function. Both during development and following exposure to salient stimuli, plasticity in the methylation of cytosine residues leads to a change in neuron excitability that subsequently sculpts animal behavior. However, although the response of DNA methyltransferase enzymes in adult neurons to stimuli such as drugs of abuse have been described, less is known about how these enzymes regulate methylation at specific loci to change the drive to ingest natural rewards. Specifically, we do not understand how changes in methylation within important brain areas known to regulate palatable food intake can affect ingestion, while a detailed investigation of the neurophysiological and genomic effects of perturbing methyltransferase function has not been pursued. By deleting DNA methyltransferase 1 and 3a in the mouse prefrontal cortex, we observed the requirement for these enzymes in the regulation of nutrient rich food consumption in the absence of any effect on the intake of low fat and low sugar chow. We also determined that the deletion profoundly affected neuron excitability within pyramidal cells resident in superficial layers II/III of the cortex but had little effect in deep layer V neurons. Finally, reduced representation bisulfite sequencing revealed both hypo and hypermethylation in response to methyltransferase deletion, an effect that was observed in binding sites for retinoic acid receptor beta (RARĪ²) located within regulatory regions of genes known to affect neuronal function. Together, our data suggest that alterations in the actions of RARĪ² could shift neuronal activity to reduce palatable food intake.Competing Interest StatementThe authors have declared no competing interest.