Aging, Environment, & DiseaseDNA Methylation and Hydroxymethylation

DNA Methylation is as Active Mark of Aging and Cognitive Impairment

DNA methylation is as active mark of aging and age-related cognitive impairment in the medial prefrontal cortexAging and age-related cognitive decline have been reported to be associated to transcriptomic alterations related to neural activity, synaptic plasticity and inflammation in specific brain regions, including the hippocampus and the medial prefrontal cortex (mPFC).1-4  Furthermore, previous epigenetic studies indicate that DNA methylation in the hippocampus is linked to cognitive function, suggesting that methylation may be a key regulator of transcriptional patterns observed in the brain.5-8  Importantly, few studies have investigated the role of epigenetics in the context of aging and cognitive function in the mPFC. Thus, to reveal connections between epigenetics, aging, and age-related cognitive decline, Thomas Foster and colleagues utilized whole genome bisulfite sequencing to profile the mPFC from young (5-6 months, n =10) and aged (17-22 months, n =20) F344 rats which were characterized in an mPFC dependent task of cognitive flexibility. A key strength from the current report9 is the correlation of DNA methylation to behavior and RNA levels from the mPFC belonging to the same animals, which were published in a separate study1.

The results from the report indicate that many sites which were differentially methylated in aging were specific to hypermethylation of genes linked to postsynaptic function and GTPase activity. Similarly, hypermethylation of genes for synaptic function, postsynaptic density, ion channel activity, and calcium channel activity were observed in aged animals that exhibited cognitive impairment. Interestingly, the majority of methylated sites were allocated to gene body regions, with intronic methylation containing the highest levels of differential methylation suggesting modification of DNA enhancer elements rather than promoters. Indeed, while DNA methylation from the gene body was reported to be positively and negatively correlated to RNA levels, down regulation of glutamate receptors genes (Grik2, Grm5, and Grm1) were correlated to hypermethylation in aged animals. Likewise, in age-impaired rats, hypermethylation of sites within synaptic genes, such as Nlgn1, Grin2b, and Stau2, were correlated to lower transcriptional levels. Thus, expression of genes required for normal brain function appear to be modified by hypermethylation of CpG sites within enhancer regions.

In summary, the study provides an extensive report of hundreds of sites where DNA methylation is likely to be an important mediator to aging and cognitive function. The findings provide specific genomic coordinates which may be further investigated through targeted approaches in epigenetics.

 
Lara Ianov1,2, Alberto Riva3, Ashok Kumar1, Thomas C. Foster1
1Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32611
2Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL 35233
3Bioinformatics Core, Interdisciplinary Center for Biotechnology Research,
University of Florida, Gainesville, FL 32611

 

Original Article:

Ianov, L., Riva, A., Kumar, A. & Foster, T. C. DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment. Frontiers in aging neuroscience 9, 249, doi:10.3389/fnagi.2017.00249 (2017).

 

References:

1. Ianov, L., Rani, A., Beas, B. S., Kumar, A. & Foster, T. C. Transcription Profile of Aging and Cognition-Related Genes in the Medial Prefrontal Cortex. Frontiers in aging neuroscience 8, 113, doi:10.3389/fnagi.2016.00113 (2016).

2. Burger, C. Region-specific genetic alterations in the aging hippocampus: implications for cognitive aging. Frontiers in aging neuroscience 2, 140, doi:10.3389/fnagi.2010.00140 (2010).

3. Blalock, E. M. et al. Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci 23, 3807-3819 (2003).

4. Rowe, W. B. et al. Hippocampal expression analyses reveal selective association of immediate-early, neuroenergetic, and myelinogenic pathways with cognitive impairment in aged rats. J Neurosci 27, 3098-3110, doi:10.1523/JNEUROSCI.4163-06.2007 (2007).

5. Day, J. J. & Sweatt, J. D. Epigenetic mechanisms in cognition. Neuron 70, 813-829, doi:10.1016/j.neuron.2011.05.019 (2011).

6. Xu, X. DNA methylation and cognitive aging. Oncotarget 6, 13922-13932, doi:10.18632/oncotarget.4215 (2015).

7. Miller, C. A., Campbell, S. L. & Sweatt, J. D. DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiology of learning and memory 89, 599-603, doi:10.1016/j.nlm.2007.07.016 (2008).

8. Hu, Y. D. et al. The cognitive impairment induced by zinc deficiency in rats aged 0 approximately 2 months related to BDNF DNA methylation changes in the hippocampus. Nutr Neurosci, 1-7, doi:10.1080/1028415X.2016.1194554 (2016).

9. Ianov, L., Riva, A., Kumar, A. & Foster, T. C. DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment. Frontiers in aging neuroscience 9, 249, doi:10.3389/fnagi.2017.00249 (2017).

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Lara Ianov

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