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. 2025 Jul 11;6(7):100646.
doi: 10.1016/j.medj.2025.100646. Epub 2025 Apr 9.

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

Mary-Jane L Ma  1 , Woody Z Zhang  1 , Peiyong Jiang  2 , Lu Ji  1 , Dongyan Xiong  1 , Wenlei Peng  1 , W K Jacky Lam  2 , Stephanie C Y Yu  1 , L Y Lois Choy  1 , Ryan Tsz-Hei Tse  3 , Suk Hang Cheng  1 , Qing Zhou  1 , Jinyue Bai  1 , Xi Hu  1 , Yuwei Shi  1 , Landon L Chan  4 , W T Charlotte Chan  1 , Pik-Ying Wong  1 , Sherwood Fung  1 , So Ling Lau  5 , John Wong  3 , Stephen L Chan  6 , Peter K F Chiu  3 , Jeremy Y C Teoh  3 , Liona C Poon  5 , Chi-Fai Ng  3 , Cheuk-Chun Szeto  7 , K C Allen Chan  2 , Y M Dennis Lo  8
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Free article

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

Mary-Jane L Ma et al. Med. .
Free article

Abstract

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.

Keywords: DNA nucleases; Foundational research; cancer detection; fragmentomics; non-invasive molecular testing; urology.

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Conflict of interest statement

Declaration of interests K.C.A.C. and Y.M.D.L. hold equities in DRA, Take2, and Insighta. W.K.J.L. and P.J. hold equities in Illumina. P.J. is a consultant to Take2. P.J. is a Director of DRA, KingMed Future, and Take2. M.-J.L.M., P.J., K.C.A.C., and Y.M.D.L. have filed a patent application based on the data presented in this study.

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