DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation

Yunyun An, Xin Zhao, Ziteng Zhang, Zhaohua Xia, Mengqi Yang, Li Ma, Yu Zhao, Gang Xu, Shunda Du, Xiang’an Wu, Shuowen Zhang, Xin Hong, Xin Jin () and Kun Sun ()
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Yunyun An: Shenzhen Bay Laboratory
Xin Zhao: Southern University of Science and Technology
Ziteng Zhang: Southern University of Science and Technology
Zhaohua Xia: Southern University of Science and Technology
Mengqi Yang: Shenzhen Bay Laboratory
Li Ma: Shenzhen Bay Laboratory
Yu Zhao: Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University
Gang Xu: West China Hospital of Sichuan University
Shunda Du: PUMC and Chinese Academy of Medical Sciences
Xiang’an Wu: PUMC and Chinese Academy of Medical Sciences
Shuowen Zhang: PUMC and Chinese Academy of Medical Sciences
Xin Hong: Southern University of Science and Technology
Xin Jin: BGI-Shenzhen
Kun Sun: Shenzhen Bay Laboratory

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Plasma cell-free DNA (cfDNA) are small molecules generated through a non-random fragmentation procedure. Despite commendable translational values in cancer liquid biopsy, however, the biology of cfDNA, especially the principles of cfDNA fragmentation, remains largely elusive. Through orientation-aware analyses of cfDNA fragmentation patterns against the nucleosome structure and integration with multidimensional functional genomics data, here we report a DNA methylation – nuclease preference – cutting end – size distribution axis, demonstrating the role of DNA methylation as a functional molecular regulator of cfDNA fragmentation. Hence, low-level DNA methylation could increase nucleosome accessibility and alter the cutting activities of nucleases during DNA fragmentation, which further leads to variation in cutting sites and size distribution of cfDNA. We further develop a cfDNA ending preference-based metric for cancer diagnosis, whose performance has been validated by multiple pan-cancer datasets. Our work sheds light on the molecular basis of cfDNA fragmentation towards broader applications in cancer liquid biopsy.

Date: 2023
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DOI: 10.1038/s41467-023-35959-6

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