Whole-genome methylation profiling of extracellular vesicle DNA in gastric cancer identifies intercellular communication features

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-08-29 DOI:10.1038/s41467-025-63435-w

Bingqian Lin, Zhenna Jiao, Shouquan Dong, Weikai Yan, Jinting Jiang, Yanfang Du, Xiaocheng Weng, Hongling Wang, Zhiyuan Hu, Yibin Liu, Xiang Zhou

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Abstract

Extracellular vesicles (EVs) are promising biomarkers for cancer diagnosis and prognosis due to their ability to carry specific biomolecular cargo, including DNA. However, the clinical utility of DNA methylation-based liquid biopsies using EV-DNA remains underexplored. The low quantity and relatively long length of EV-DNA complicate whole-genome methylation profiling. To address this, we develop Tn5-assisted Enzymatic Methyl-sequencing with Post-conversion Tailing (TEMPT), a bisulfite-free whole-genome profiling method for EV-DNA. TEMPT employs single-adapter Tn5 tagmentation, enzymatic conversion of unmodified cytosines, and post-conversion tailing to generate high-depth whole-genome EV-DNA methylomes. We apply TEMPT to EV-DNA from 58 gastric cancer and polyp samples, generating methylomes from sub-nanogram inputs and identifying differentially methylated regions (DMRs) that distinguish cancer from controls. We identify potential cancer biomarkers through DMR-associated genes, highlighting the roles of EVs in cellular communication. Our findings suggest that immune cells may serve as an alternative source of EV-DNA. This approach holds significant promise for advancing EV-DNA research and its applications in early disease diagnosis.

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胃癌细胞外囊泡DNA的全基因组甲基化分析鉴定细胞间通讯特征

细胞外囊泡（EVs）由于能够携带特定的生物分子货物，包括DNA，是癌症诊断和预后的有前途的生物标志物。然而，使用EV-DNA进行DNA甲基化液体活检的临床应用仍未得到充分探索。EV-DNA的低数量和相对较长的长度使全基因组甲基化分析复杂化。为了解决这个问题，我们开发了tn5辅助酶促甲基测序与转换后尾化（TEMPT），这是一种无亚硫酸盐的EV-DNA全基因组分析方法。TEMPT采用单适配器Tn5标记、未修饰胞嘧啶的酶转化和转化后的尾尾来产生高深度的全基因组EV-DNA甲基化。我们将TEMPT应用于58个胃癌和息肉样本的EV-DNA，从亚纳克输入产生甲基组，并鉴定区分癌症和对照的差异甲基化区域（DMRs）。我们通过dmr相关基因识别潜在的癌症生物标志物，强调ev在细胞通讯中的作用。我们的研究结果表明，免疫细胞可能是EV-DNA的另一种来源。这种方法对推进EV-DNA研究及其在早期疾病诊断中的应用具有重要的前景。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.