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

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

doi:10.1016/j.medj.2025.100646

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

Med. 2025 Apr 4:100646. doi: 10.1016/j.medj.2025.100646. Online ahead of print.

Authors

Mary-Jane L Ma¹, Woody Z Zhang¹, Peiyong Jiang², Lu Ji¹, Dongyan Xiong¹, Wenlei Peng¹, W K Jacky Lam², Stephanie C Y Yu¹, L Y Lois Choy¹, Ryan Tsz-Hei Tse³, Suk Hang Cheng¹, Qing Zhou¹, Jinyue Bai¹, Xi Hu¹, Yuwei Shi¹, Landon L Chan⁴, W T Charlotte Chan¹, Pik-Ying Wong¹, Sherwood Fung¹, So Ling Lau⁵, John Wong³, Stephen L Chan⁶, Peter K F Chiu³, Jeremy Y C Teoh³, Liona C Poon⁵, Chi-Fai Ng³, Cheuk-Chun Szeto⁷, K C Allen Chan², Y M Dennis Lo⁸

Affiliations

¹ Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
² Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
³ Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
⁴ Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
⁵ Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
⁶ State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China; Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
⁷ Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
⁸ Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China. Electronic address: loym@cuhk.edu.hk.

PMID: 40209704
DOI: 10.1016/j.medj.2025.100646

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.