Environmental enrichment modulates 5-hydroxymethylcytosine dynamics in hippocampus

Abstract

Gene-environment interactions mediated at the epigenetic level may provide an initial step in delivering an appropriate response to environmental changes. 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC), accounts for ~40% of modified cytosine in brain and has been implicated in DNA methylation-related plasticity. To identify the role of 5hmC in gene-environment interactions, we exposed both young (6-week-old) and aged (18-month-old) mice to both an enriched environment and a standard environment. Exposure to EE significantly improves learning and memory in aged mice and reduces 5hmC abundance in mouse hippocampus. Furthermore, we mapped the genome-wide distribution of 5hmC and found that the alteration of 5hmC modification occurred mainly at gene bodies. In particular, genes involved in axon guidance are enriched among the genes with altered 5hmC modification. These results together suggest that environmental enrichment could modulate the dynamics of 5hmC in hippocampus, which could potentially contribute to improved learning and memory in aged animals.

DNA cytosine hydroxymethylation levels are distinct among non-overlapping classes of peripheral blood leukocytes

“…A current view is that high levels of gene region specific 5hmCG potentiate genes for “ on demand gene regulation ”(Irier et al, 2014). Further, there is direct evidence that this cytosine modification is essential for normal regulation of gene expression.…”

Physical exercise as an epigenetic modulator of brain plasticity and cognition

“…Interestingly, a previous study showed that aged mice exposed to environmental enrichment - a procedure known to elicit positive brain changes based on its physical activity component - had an improvement in learning and memory as well as a reduction in 5hmC abundance in the hippocampus (Irier et al, 2014). Altogether, these findings indicate that an enhancement of physical activity levels can reprogram the brain's methylation pattern to modulate the transcription of genes necessary for the maintenance of brain health and cognitive function.…”

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

“…The GO and KEGG enrichment analysis for the probes in the 'yellowgreen' module highlighted many pathways associated with the pathophysiology of cognitive dysfunction and dementia (Supplementary Tables 4 & 5), for example, the GO terms 'main axon' (GO:0044304: p = 4.37E-03) and 'β-amyloid binding' (GO:0001540: p = 0.0109), and the KEGG pathways 'glutamatergic synapse' (hsa04727: p = 4.79E-04) and 'Alzheimer's disease' (hsa05010: p = 0.0491). DNAm and hydroxymethylation changes in genes involved in these pathways, such as axon and glutamatergic synapse have been previously linked to brain aging and cognition in experimental models [44,45].…”