Scalable screening of ternary-code DNA methylation dynamics associated with human traits

Area of Science:

• Epigenetics and Genomics
• Human Trait Association
• Biomarker Discovery

Background:

• Epigenome-wide association studies (EWASs) are crucial for understanding epigenetics in complex human traits.
• Current methods may not fully capture the complexity of DNA modifications.
• Integrating diverse methylation signatures is needed for comprehensive analysis.

Purpose of the Study:

• To introduce a novel tool, the methylation screening array (MSA), for scalable screening of DNA cytosine modifications.
• To investigate the role of 5-hydroxymethylcytosine (5hmC) alongside 5-methylcytosine (5mC) in human traits and epigenetic clocks.
• To explore cell-type-specific epigenetic regulation and aging dynamics.

Main Methods:

• Development and application of the methylation screening array (MSA) for profiling DNA methylations (5mC, 5hmC, unmodified cytosine).
• Integration of EWASs with cell-type-linked methylation signatures.
• Comparative analysis of EWAS and genome-wide association study (GWAS) hits within specific cell-type contexts.

Main Results:

• The MSA enables quantitative screening of trait-associated DNA modifications in large populations.
• 5hmC plays a significant role in mediating human trait associations and epigenetic clocks, complementing 5mC.
• Identified shared and tissue-specific 5hmC aging dynamics and methylation changes.

Conclusions:

• The MSA is a powerful tool for advancing EWAS research and understanding epigenetic regulation.
• 5hmC is a critical epigenetic mark with previously unappreciated roles in human health and disease.
• Findings provide a comprehensive landscape of cytosine modifications in human tissues, impacting aging and disease research.