Blood cell-free DNA (cfDNA) is derived from fragmented chromatin in dying cells. As such, it remains associated with histones that may retain the covalent modifications present in the cell of origin. Until now this rich epigenetic information carried by cell-free nucleosomes has not been explored at the genome level. Here, we perform ChIP-seq of cell free nucleosomes (cfChIP-seq) directly from human blood plasma to sequence DNA fragments from nucleosomes carrying specific chromatin marks. We assay a cohort of healthy subjects and patients and use cfChIP-seq to generate rich sequencing libraries from low volumes of blood. We find that cfChIP-seq of chromatin marks associated with active transcription recapitulates ChIP-seq profiles of the same marks in the tissue of origin, and reflects gene activity in these cells of origin. We demonstrate that cfChIP-seq detects changes in expression programs in patients with heart and liver injury or cancer. cfChIP-seq opens a new window into normal and pathologic tissue dynamics with far-reaching implications for biology and medicine.

ChIP-seq of plasma cell-free nucleosomes identifies cell-of-origin gene expression programs