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Epigenetics Chromatin. 2019 Oct 8;12(1):58. doi: 10.1186/s13072-019-0306-5.

Early-life DNA methylation profiles are indicative of age-related transcriptome changes.

Author information

1
Oklahoma Center for Neuroscience, Oklahoma City, OK, USA.
2
Reynolds Oklahoma Center on Aging, SLY-BRC 1370, 975 NE 10th St, Oklahoma City, OK, 73104, USA.
3
The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
4
Department of Physiology, Oklahoma City, OK, USA.
5
Oklahoma Nathan Shock Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
6
Oklahoma Center for Neuroscience, Oklahoma City, OK, USA. wfreeman@ouhsc.edu.
7
Reynolds Oklahoma Center on Aging, SLY-BRC 1370, 975 NE 10th St, Oklahoma City, OK, 73104, USA. wfreeman@ouhsc.edu.
8
Department of Physiology, Oklahoma City, OK, USA. wfreeman@ouhsc.edu.
9
Oklahoma Nathan Shock Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. wfreeman@ouhsc.edu.
10
Oklahoma City VA Medical Center, Oklahoma City, OK, 73104, USA. wfreeman@ouhsc.edu.

Abstract

BACKGROUND:

Alterations to cellular and molecular programs with brain aging result in cognitive impairment and susceptibility to neurodegenerative disease. Changes in DNA methylation patterns, an epigenetic modification required for various CNS functions are observed with brain aging and can be prevented by anti-aging interventions, but the relationship of altered methylation to gene expression is poorly understood.

RESULTS:

Paired analysis of the hippocampal methylome and transcriptome with aging of male and female mice demonstrates that age-related differences in methylation and gene expression are anti-correlated within gene bodies and enhancers. Altered promoter methylation with aging was found to be generally un-related to altered gene expression. A more striking relationship was found between methylation levels at young age and differential gene expression with aging. Highly methylated gene bodies and promoters in early life were associated with age-related increases in gene expression even in the absence of significant methylation changes with aging. As well, low levels of methylation in early life were correlated to decreased expression with aging. This relationship was also observed in genes altered in two mouse Alzheimer's models.

CONCLUSION:

DNA methylation patterns established in youth, in combination with other epigenetic marks, were able to accurately predict changes in transcript trajectories with aging. These findings are consistent with the developmental origins of disease hypothesis and indicate that epigenetic variability in early life may explain differences in aging trajectories and age-related disease.

KEYWORDS:

Aging; DNA methylation; Epigenetics; Gene regulation; Hippocampus

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