Urine cf-nucleosomes: A non-invasive window into human physiology and disease.

Urine contains fragments of cell-free DNA (cfDNA) that offer molecular insights into processes within the urinary system and the body. It remains unclear whether these fragments exist as chromatin and retain chromatin modifications from their cells of origin. Here, we employ cell-free chromatin immunoprecipitation followed by sequencing (cfChIP-seq) on human urine to address this issue. We show that cf-nucleosomes can be captured from urine and preserve histone modifications associated with gene activation and repression. Analysis in healthy individuals reveals distinct tissue contributions to urine cf-nucleosomes, including a kidney-derived population not detected in matched exfoliated cells or plasma. This suggests that kidney filtration largely excludes plasma cf-nucleosomes. In patients with bladder cancer, urine cf-nucleosomes reflect tumor-associated transcriptional programs and immune responses. These findings highlight the utility of urine cf-nucleosomes as accessible, non-invasive biomarkers for studying renal physiology and monitoring urinary pathologies.