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

An，Yunyun1; Zhao，Xin2; Zhang，Ziteng2; Xia，Zhaohua3; Yang，Mengqi1; Ma，Li1; Zhao，Yu4; Xu，Gang5; Du，Shunda6; Wu，Xiang’an6; Zhang，Shuowen6; Hong，Xin7; Jin，Xin8,9; Sun，Kun1

2023-12-01

10.1038/s41467-023-35959-6

Nature Communications   Impact Factor & Quartile

2041-1723

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.

English

NI Journal Papers

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National Outstanding Youth Science Fund Project of National Natural Science Foundation of China[82101763];

2-s2.0-85146485552

Scopus

1.Institute of Cancer Research,Shenzhen Bay Laboratory,Shenzhen,518132,China
2.Hepato-Biliary Surgery Division,Shenzhen Third People’s Hospital,The Second Affiliated Hospital,Southern University of Science and Technology,Shenzhen,518100,China
3.Thoracic Surgical Department,Shenzhen Third People’s Hospital,The Second Affiliated Hospital,Southern University of Science and Technology,Shenzhen,518100,China
4.Molecular Cancer Research Center,School of Medicine,Sun Yat-sen University,Shenzhen,Shenzhen Campus of Sun Yat-sen University,518107,China
5.Department of Liver Surgery and Liver Transplant Center,West China Hospital of Sichuan University,Chengdu,610041,China
6.Department of Liver Surgery,Peking Union Medical College Hospital,PUMC and Chinese Academy of Medical Sciences,Beijing,Dongcheng,100730,China
7.Department of Biochemistry,School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
8.BGI-Shenzhen,Shenzhen,518083,China
9.School of Medicine,South China University of Technology,Guangzhou,Guangdong,510006,China

An，Yunyun,Zhao，Xin,Zhang，Ziteng,et al. DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation[J]. Nature Communications,2023,14(1).

An，Yunyun.,Zhao，Xin.,Zhang，Ziteng.,Xia，Zhaohua.,Yang，Mengqi.,...&Sun，Kun.(2023).DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation.Nature Communications,14(1).

An，Yunyun,et al."DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation".Nature Communications 14.1(2023).