Local CpG density affects the trajectory and variance of age-associated DNA methylation changes

Area of Science:

• Epigenetics
• Genomics
• Aging Research

Background:

• DNA methylation is a key epigenetic regulator of gene expression.
• Age-related changes in DNA methylation patterns are used in epigenetic clocks to predict biological age.
• The molecular drivers of age-associated DNA methylation alterations are not fully understood.

Purpose of the Study:

• To investigate the factors driving age-associated DNA methylation changes at individual CpG sites.
• To understand the role of local DNA sequence in epigenetic aging.

Main Methods:

• Analysis of longitudinal DNA methylation trajectories from 600 individuals (aged 67-80) at 345,895 CpGs.
• Examination of changes at low CpG density loci and their association with single nucleotide polymorphisms (SNPs).

Main Results:

• Age-associated methylation changes occurred at 182,760 loci, largely independent of cell type variations.
• Low CpG density regions (8322 loci) showed prominent age-related changes, with 1487 influenced by local sequence polymorphisms.
• These low CpG density regions exhibited variable methylation changes in individuals over 65, contrasting with predominant methylation loss in younger individuals.

Conclusions:

• Local DNA sequence significantly influences in vivo age-associated DNA methylation changes in humans.
• CpG interactions may reinforce methylation patterns in dense regions, explaining stability.
• Findings highlight the role of sequence context in epigenetic drift during aging.