Chromatin accessibility states affect transrenal clearance of plasma DNA: Implications for urine-based diagnostics

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BACKGROUND: Urinary cell-free DNA (ucfDNA) is a valuable resource for truly non-invasive liquid biopsy. UcfDNA comprises transrenal ucfDNA passing from the bloodstream through the glomeruli and locally shed urinary-tract ucfDNA. Understanding their differences in characteristics may enable new diagnostic applications. METHODS: We analyzed 136 ucfDNA samples from healthy controls, pregnant women, patients with chronic kidney diseases (CKDs), and bladder cancer using massively parallel sequencing. Fragmentomic characteristics including fragment sizes and 5' end motifs were deduced. The relationship between ucfDNA and chromatin accessibility was examined by overlapping ucfDNA with open chromatin regions (OCRs, lacking histones) and heterochromatin regions (HCRs, tightly packed with histones). FINDINGS: Compared with urinary-tract ucfDNA, the transrenal ucfDNA was shorter and enriched for C-ends. The transrenal ucfDNA was over-represented in OCRs but depleted in HCRs, indicating an interplay between the glomerular filtration barrier and the effective cfDNA size. In patients with proteinuria (preeclampsia and CKDs), the amount of ucfDNA from HCRs increased, suggesting elevated glomerular permeability of histone-bound plasma DNA molecules. In oncology, the use of hypomethylation signals in HCRs enhanced bladder cancer detection, with an area under the receiver operating characteristic curve of 0.93. CONCLUSIONS: Chromatin accessibility states impact the transrenal clearance of plasma DNA, likely through the size restriction of the glomerular barrier. This realization has enabled the rational development of novel approaches for detecting or monitoring renal dysfunction and urological cancers. FUNDING: The Innovation and Technology Commission of the Hong Kong SAR Government (InnoHK initiative) and the Li Ka Shing Foundation supported this study.

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