Will it rain tomorrow? Will I ever win the lottery? Will our new paper finally be accepted!? Unfortunately, we have yet to come up with a sturdy means to predict our fates far in the future; however, new research by Hadad and colleagues now suggests that DNA methylation profiles in young cells accurately foretell changes to transcriptional profiles later in life!
Specifically, the team led by Willard M. Freeman (University of Oklahoma, USA) set out to understand the aging-related cellular and molecular programs that contribute to cognitive impairment and susceptibility to neurodegenerative disease by studying how changes to male and female mouse hippocampal DNA methylation profiles during aging correlate to gene expression.
Instead of crystal balls and tarot cards, the authors employed whole-genome bisulfite sequencing (WGBS) and RNA-sequencing to provide a more precise vision of how epigenetic patterns in young cells “foretell” future hippocampal transcription and inform on the risk of neurodegenerative disease:
- Overall, the authors failed to uncover a robust link between age-related differentially methylated regions in hippocampal cells and the transcriptional changes that occur with age, suggesting that methylation during aging serves a more complex role in transcriptional regulation
- Differential methylation within the gene body and enhancer elements does inversely correlate with gene expression during aging in mouse hippocampi, although this weak relationship accounts for only a small fraction of the differentially expressed genes with aging
- Alterations to promoter methylation with aging do not correlate with alterations to gene expression
- Further analysis of gene body methylation levels and gene expression uncovered that DNA methylation patterns established during early life strongly correlate with differential gene expression later in life
- High DNA methylation in early life leads to increases in gene expression later in life (even in the absence of significant methylation changes during aging) while low DNA methylation in early life leads to later decreases in gene expression
- Pathways showing the highest correlation between DNA methylation patterns and transcriptional change with age include those involved with inflammation, oxidative stress, proteolysis, cell senescence, epigenetic regulation, and estrogen signaling.
- Affected genes include those that display alterations in mouse models of Alzheimer’s disease, suggesting that genes that show differential regulation during neurodegeneration may be more susceptible to change due to their methylation profile early in life
The authors believe that the early programming of the epigenome can influence whether gene expression will change with age and the directionality of the change; however, they do note the need to test predictive validity with bigger data sets and refined locations for transcriptional start sites, alternative splice sites, and gene regulatory marks.
Can a deeper understanding of epigenetic profiles during development provide a future forecast of later-life molecular responses in the central nervous system and disease susceptibility?