Jagged Ends on Multinucleosomal Cell-Free DNA Serve as a Biomarker for Nuclease Activity and Systemic Lupus Erythematosus

Autor: Spencer C Ding, Rebecca W Y Chan, Wenlei Peng, Liangbo Huang, Ze Zhou, Xi Hu, Stefano Volpi, Linda T Hiraki, Augusto Vaglio, Paride Fenaroli, Paola Bocca, Lai Shan Tam, Priscilla C H Wong, Lydia H P Tam, Peiyong Jiang, Rossa W K Chiu, K C Allen Chan, Y M Dennis Lo
Rok vydání: 2022
Předmět:
Zdroj: Clinical Chemistry. 68:917-926
ISSN: 1530-8561
0009-9147
DOI: 10.1093/clinchem/hvac050
Popis: Background Jagged ends of plasma DNA are a recently recognized class of fragmentomic markers for cell-free DNA, reflecting the activity of nucleases. A number of recent studies have also highlighted the importance of jagged ends in the context of pregnancy and oncology. However, knowledge regarding the generation of jagged ends is incomplete. Methods Jaggedness of plasma DNA was analyzed based on Jag-seq, which utilized the differential methylation signals introduced by the DNA end-repair process. We investigated the jagged ends in plasma DNA using mouse models by deleting the deoxyribonuclease 1 (Dnase1), DNA fragmentation factor subunit beta (Dffb), or deoxyribonuclease 1 like 3 (Dnase1l3) gene. Results Aberrations in the profile of plasma DNA jagged ends correlated with the type of nuclease that had been genetically deleted, depending on nucleosomal structures. The deletion of Dnase1l3 led to a significant reduction of jaggedness for those plasma DNA molecules involving more than 1 nucleosome (e.g., size ranges 240-290 bp, 330-380 bp, and 420-470 bp). However, less significant effects of Dnase1 and Dffb deletions were observed regarding different sizes of DNA fragments. Interestingly, the aberration in plasma DNA jagged ends related to multinucleosomes was observed in human subjects with familial systemic lupus erythematosus with Dnase1l3 deficiency and human subjects with sporadic systemic lupus erythematosus. Conclusions Detailed understanding of the relationship between nuclease and plasma DNA jaggedness has opened up avenues for biomarker development.
Databáze: OpenAIRE
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