Scalable Screening of Ternary-Code DNA Methylation Dynamics Associated with Human Traits.

Area of Science:

• Epigenetics and Genomics
• Human Population Studies
• Molecular Biology

Background:

• Epigenome-wide association studies (EWAS) are crucial for understanding epigenetics in complex human traits.
• Existing technologies face limitations in scalability and the analysis of nuanced cytosine modifications.

Purpose of the Study:

• Introduce the Methylation Screening Array (MSA) for scalable, quantitative screening of trait associations.
• Integrate EWAS, single-cell, and cell-type-resolved methylome profiles.
• Investigate the roles of 5-hydroxymethylcytosine (5hmC) and 5-methylcytosines (5mCs) in human traits and aging.

Main Methods:

• Development and application of the Methylation Screening Array (MSA).
• Integration of EWAS, single-cell, and cell-type-resolved methylome data.
• Comprehensive human 5hmC aging EWAS analysis.

Main Results:

• MSA enables scalable screening of ternary-code cytosine modifications in diverse populations.
• Revealed a significant role for 5hmC in trait associations and epigenetic clocks.
• Demonstrated 5hmC and 5mC interplay in defining epigenetic identities and highlighted cell-type context for EWAS/GWAS.
• Identified tissue-invariant and tissue-specific aging dynamics, including distinct mitotic methylation rates.

Conclusions:

• MSA is a powerful platform for advancing epigenetics research in large human cohorts.
• 5hmC plays a critical, previously unappreciated role in human traits, cell identity, and aging.
• Understanding the interplay of 5hmC and 5mC is essential for comprehending health and disease.