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Front Aging Neurosci. 2017 Aug 2;9:249. doi: 10.3389/fnagi.2017.00249. eCollection 2017.

DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment.

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Department of Neuroscience, McKnight Brain Institute, University of Florida, GainesvilleFL, United States.
Genetics and Genomics Program, Genetics Institute, University of Florida, GainesvilleFL, United States.
Bioinformatics Core, Interdisciplinary Center for Biotechnology Research, University of Florida, GainesvilleFL, United States.


The current study investigates DNA methylation as a possible epigenetic regulator of transcription associated with aging and cognitive function. Young and aged male Fischer 344 rats were behaviorally characterized on a set shifting task, and whole genome bisulfite sequencing was employed to profile the DNA methylome of the medial prefrontal cortex (mPFC). DNA methylation was also compared to RNA expression in the mPFC from the same animals. Variability in methylation was mainly observed for CpG sites as opposed to CHG and CHH sites. Gene bodies, specifically introns, contain the highest levels of methylation. During aging, hypermethylation was observed for genes linked to synaptic function and GTPase activity. Furthermore, impaired cognitive flexibility during aging was associated with hypermethylation of genes linked to postsynaptic density, dendrites, the axon terminus, and Ca2+ channels. Finally, comparison with RNA expression confirmed that hypermethylation was correlated with decreased expression of synaptic genes. The results indicate that DNA methylation over the lifespan contributes to synaptic modification observed in brain aging and age-related cognitive impairment.


aging; cognitive flexibility; epigenetics; prefrontal cortex; set shifting task

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