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Epigenetic regulation of DNA base excision repair during ageing and dietary restriction

Published online by Cambridge University Press:  30 August 2013

J. Górniak ,
S. A. S. Langie ,
K. M. Cameron ,
T. von Zglinicki ,
J. Mann ,
D. M. Pachen ,
R. W. L. Godschalk  and
J. C. Mathers
J. Górniak
Affiliation:
Centre for Brain Ageing and Vitality, Human Nutrition Research Centre, Newcastle University, NE4 5PL
S. A. S. Langie
Affiliation:
Centre for Brain Ageing and Vitality, Human Nutrition Research Centre, Newcastle University, NE4 5PL
K. M. Cameron
Affiliation:
Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, NE4 5PL
T. von Zglinicki
Affiliation:
Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, NE4 5PL
J. Mann
Affiliation:
Institute of Cellular Medicine, Newcastle University, NE2 2NN
D. M. Pachen
Affiliation:
Department of Health and Risk Analysis and Toxicology, Maastricht University, The Netherlands
R. W. L. Godschalk
Affiliation:
Department of Health and Risk Analysis and Toxicology, Maastricht University, The Netherlands
J. C. Mathers
Affiliation:
Centre for Brain Ageing and Vitality, Human Nutrition Research Centre, Newcastle University, NE4 5PL Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, NE4 5PL
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Abstract

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Base excision repair (BER) is the primary mechanism used to fix oxidative damage to DNA. However BER efficiency declines with age( Reference Intano, Cho and McMahan 1 , Reference Swain and Rao2 ). To determine whether epigenetic events contribute to the ageing process through deregulation of BER gene expression we quantified DNA methylation and histone acetylation at BER-gene promoters (Ogg1 and Apex) and BER repair activity in ageing and dietary restricted (DR) mice.

We measured promoter methylation by pyrosequencing in brain and livers from ad libitum (AL) and 40% DR mice at 3, 12, 24 and 30 months of age (n=5–7/group). Ogg1 promoter methylation decreased with age in the liver (p=0.018) and brain (p=0.016) and DR reduced Ogg1 methylation (p=0.014) in the brain. At 30 mo, we observed a 2.5 fold enrichment in histone 4 acetylation as measured by the ChIP assay in liver Ogg1 promoter (p=0.004) and a 2 fold enrichment at Ogg1 (p=0.02) and Apex promoters (p=0.031) in the brain. Ogg1 expression in the liver decreased by 40% with age and DR (p=0.0031) and with DR only in the brain (p=0.002). Apex expression did not change with age but was lower in DR animals (p=0.003). A comet-based in vitro assay for BER incision activity( Reference Langie, Cameron and Waldron 3 ) revealed no significant changes in either tissue. 8-oxoguanine lesions measured by HPLC-ECD decreased with age (p<0.001) in the liver but not in the brain.

Table 1.

Summary of results from the liver

Table 2.

Summary of results from the brain

In summary, our data suggest that epigenetic processes may contribute to transcriptional changes in BER-related genes during ageing and with DR.

This work was funded by the Research Councils through the Lifelong Health and Wellbeing Initiative.

References

1. Intano, GW, Cho, EJ, McMahan, et al. (2003) J Gerontol A Biol Sci Med Sci 58, B205–B211.CrossRefGoogle Scholar
2. Swain, U & Rao, KS (2012) Mech Ageing Dev 133, 186–194.CrossRefGoogle Scholar
3. Langie, SAS, Cameron, KM, Waldron, KJ et al. (2011) Mutagenesis 26, 461–71.Google Scholar
Figure 0

Table 1. Summary of results from the liver

Figure 1

Table 2. Summary of results from the brain