Regulatory mode and enhancer architecture determine limits of blood DNA methylation as a molecular proxy

Distal CpGs in T-cell enhancer chromatin states drive methylation-based prediction of lineage-identity gene expression, while dynamically regulated cytokine and immune checkpoint ligand genes remain weakly predictable.

• Why it matters: Blood DNA methylation models are used as surrogates for traits, but it is unclear whether the CpGs reflect true regulatory biology or merely statistical convenience.
• What they did: Elastic-net models were trained on 333 matched T-cell enriched blood samples using expression of 77 T cell genes, then CpG locations and chromatin-state enrichment were audited; methylation-predicted expression was tested against NanoString in an independent 228-sample cancer cohort.
• The result: Methylation-predicted expression stayed highly concordant for lineage genes but only weakly concordant for stimulus-responsive checkpoint ligands, implying biomarker limits depend on regulatory mode rather than modeling choices.

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