Epigenomic modifications define chromatin states to regulate cell-free DNA fragmentomics

Plasma cell-free DNA (cfDNA) fragmentomics offer promising cancer biomarkers, but their molecular regulation remains elusive. Here, we investigate the role of epigenomic modifications in cfDNA fragmentation. We identify strong correlations between cfDNA fragmentomic features and various epigenetic marks measured in cfDNA. We further segment the genome into different chromatin states using histone modification signals, revealing consistent associations with cfDNA fragmentomics. The association is further validated by histone modifier perturbation experiments, confirming chromatin organization as a key regulator of cfDNA fragmentation. CfDNA fragmentomic features associated with Transposon Elements (TEs) outperform genome-wide metrics in cancer diagnosis, reflecting cancer type-specific patterns. Leveraging these insights, we develop TEANA (Transposon Element Analysis in cfDNA), an AI-empowered model using a small set of TE fragmentomic features for pan-cancer detection and tumor-origin prediction, achieving robust performance across independent cohorts. Hence, chromatin states drive cfDNA fragmentation, and dysregulated TEs provide highly informative biomarkers for cancer diagnosis.