Distinct Cellular and Molecular Environments Support Aging-Related DNA Methylation Changes in the Substantia Nigra

Abstract

Aim: We aimed to couple brain region-specific changes in global DNA methylation over aging to underlying cellular and molecular environments. Materials & methods: We measured two major forms of DNA methylation and analyzed Dnmt, Tet and metabolite levels in the striatum and substantia nigra (SN) over aging in healthy male mice. Results: The ratio of 5-hydroxymethylcytosine to 5-methylcytosine increases over aging in the SN, and 5-hydroxymethylcytosine increases preferentially in dopaminergic neurons. Additionally, this age-dependent alteration in methylation correlates with a reduction in the ratio of α-ketoglutarate to succinate in the SN. Conclusion: Distinct cellular and molecular environments correlate with aging-associated methylation changes in the SN, implicating this epigenetic mechanism in the susceptibility of this brain region to age-related cell loss.

Keywords::

• 5-hydroxymethylcytosine
• 5-methylcytosine
• α-ketoglutarate
• aging
• DNA methylation
• DNMTs
• dopaminergic
• striatum
• substantia nigra
• TETs

Financial & competing interests disclosure

This work was supported in part by the NIH (R21 ES025392 to Y Wang and R01 MH091850 to Z Zhou). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all animal experimental investigations.

Additional information

Funding

This work was supported in part by the NIH (R21 ES025392 to Y Wang and R01 MH091850 to Z Zhou). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.