DNA methylation-environment interactions in the human genome.

Area of Science:

• Genomics
• Epigenetics
• Molecular Biology

Background:

• DNA methylation is a key epigenetic mechanism influencing gene regulation.
• Understanding how DNA methylation interacts with environmental factors is crucial for deciphering cellular responses.
• Previous methods allowed testing of millions of loci but lacked comprehensive genomic coverage.

Approach:

• Applied massively parallel reporter assay sequencing (mSTARR-seq) to query nearly the entire human genome.
• Investigated millions of CpG sites, including those on the Illumina MethylationEPIC array and via reduced representation bisulfite sequencing.
• Assessed regulatory capacity and methylation-dependent activity in response to interferon alpha (IFNA) stimulation.

Key Points:

• Fragments containing CpG sites are enriched for regulatory capacity.
• Methylation-dependent regulatory activity is sensitive to the cellular environment, particularly IFNA stimulation.
• DNA methylation attenuates regulatory responses to IFNA, indicating widespread DNA methylation-environment interactions.
• Methylation-dependent responses to IFNA predict transcriptional responses to influenza virus in human macrophages.

Conclusions:

• Pre-existing DNA methylation patterns can influence responses to subsequent environmental exposures, supporting biological embedding.
• Widespread DNA methylation-environment interactions were identified.
• No significant enrichment was found for functional influence on gene regulation at sites associated with early life adversity.