Nuclease deficiencies alter plasma cell-free DNA methylation profiles.
Nuclease deficiencies alter plasma cell-free DNA methylation profiles.
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DOI：
10.1101/gr.275426.121
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发表时间：
2021-11
期刊：
影响因子：
7
通讯作者：
Lo YMD
中科院分区：
文献类型：
--
作者：
Han DSC;Ni M;Chan RWY;Wong DKL;Hiraki LT;Volpi S;Jiang P;Lui KO;Chan KCA;Chiu RWK;Lo YMD
在这些核酸酶缺陷的小鼠和DNASE1L3缺陷的人的血浆中探索了DNASE1L3或DNASE1缺陷对无细胞DNA（cfDNA）甲基化的影响。与野生型cfDNA相比，DNASE1L3缺陷小鼠中的cfDNA显著低甲基化，而DNASE1缺陷小鼠中的cfDNA高甲基化。DNASE1L3缺陷小鼠中的cfDNA低甲基化是由于来自开放染色质区域（OCR）和CpG岛（CGI）的片段化和代表性增加。这些发现在DNASE1缺陷小鼠中不存在，证明了DNASE1在低甲基化的OCR和CGI中切割的偏好。我们还观察到在不存在DNASE1L3的情况下，甲基化CpG的片段末端显著减少，从而证明DNASE1L3更喜欢在甲基化CpG处切割。此外，我们发现cfDNA的甲基化水平随片段大小以周期性模式变化，特定大小的cfDNA更低甲基化并且富集OCR和CGI。这些发现在DNASE1L3缺陷型人cfDNA中得到证实。因此，我们发现核酸酶介导的cfDNA片段化在全基因组范围内显著影响cfDNA甲基化水平。这项工作为甲基化、核酸酶生物学和cfDNA片段化之间的关系提供了基础性理解。
The effects of DNASE1L3 or DNASE1 deficiency on cell-free DNA (cfDNA) methylation were explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wild-type cfDNA, cfDNA in DNASE1L3-deficient mice was significantly hypomethylated, while cfDNA in DNASE1-deficient mice was hypermethylated. The cfDNA hypomethylation in DNASE1L3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in DNASE1-deficient mice, demonstrating the preference of DNASE1 to cleave in hypomethylated OCRs and CGIs. We also observed a substantial decrease of fragment ends at methylated CpGs in the absence of DNASE1L3, thereby demonstrating that DNASE1L3 prefers to cleave at methylated CpGs. Furthermore, we found that methylation levels of cfDNA varied by fragment size in a periodic pattern, with cfDNA of specific sizes being more hypomethylated and enriched for OCRs and CGIs. These findings were confirmed in DNASE1L3-deficient human cfDNA. Thus, we have found that nuclease-mediated cfDNA fragmentation markedly affects cfDNA methylation level on a genome-wide scale. This work provides a foundational understanding of the relationship between methylation, nuclease biology, and cfDNA fragmentation.
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通讯作者：
Lo YMD