The DNA methylome of human vascular endothelium and its use in liquid biopsies.
The DNA methylome of human vascular endothelium and its use in liquid biopsies.
复制标题
人血管内皮 DNA 甲基化及其在液体活检中的应用。
DOI：
10.1016/j.medj.2023.03.006
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Venn,O
中科院分区：
文献类型：
--
作者：
Peretz,Ayelet;Loyfer,Netanel;Piyanzin,Sheina;Ochana,BrachaLea;Neiman,Daniel;Magenheim,Judith;Klochendler,Agnes;Drawshy,Zeina;Fox-Fisher,Ilana;Fridlich,Ori;Moss,Joshua;Cohen,Daniel;Zemmour,Hai;Cann,Gordon;Bredno,Joerg;Venn,O
背景资料：血管内皮细胞（VEC）是每个组织的重要组成部分，有助于多种病理，并被重要药物靶向。然而，有一个短缺的生物标志物，以评估VEC turning.Methods：为了开发DNA甲基化为基础的液体活检VEC，我们确定了从新鲜分离的人类tissues.Findings的VEC的甲基化：与人类细胞型甲基化图谱的比较产生了数千个位点，是独特的未甲基化的VEC。这些位点通常是基因增强子，通常位于VEC特异性基因附近。我们还确定了数百个基因组位点的差异甲基化的器官型血管内皮细胞，表明血管内皮细胞喂养特定的器官是不同的细胞类型，具有稳定的表观遗传特性。我们建立了通用和肺特异性VEC标记物，并评估了它们在循环无细胞DNA（cfDNA）中的存在。健康个体血浆中近2.5%的cfDNA来源于VEC。败血症、移植物抗宿主病和心导管插入术与VEC衍生的cfDNA水平升高相关，指示血管损伤。肺特异性VEC cfDNA在慢性阻塞性肺疾病（COPD）或肺癌患者中选择性升高，揭示了组织特异性血管更新。结论：VEC cfDNA生物标志物为健康和疾病中的血管动力学提供信息，可能有助于病理的早期诊断和监测，以及药物活性的评估。这项工作得到了Beutler研究计划，Helmsley慈善信托基金，JDRF，Grail和DON基金会的支持。Y.D担任Walter & Greta Stiel心脏研究主席。B.G.，我是说，R.S.：J. M.，D.N.，TK和Y.D.申请了cfDNA分析的专利
Background: Vascular endothelial cells (VECs) are an essential component of each tissue, contribute to multiple pathologies, and are targeted by important drugs. Yet, there is a shortage of biomarkers to assess VEC turnover.Methods: To develop DNA methylation-based liquid biopsies for VECs, we determined the methylome of VECs isolated from freshly dissociated human tissues.Findings: A comparison with a human cell-type methylome atlas yielded thousands of loci that are uniquely unmethylated in VECs. These sites are typically gene enhancers, often residing adjacent to VEC-specific genes. We also identified hundreds of genomic loci that are differentially methylated in organotypic VECs, indicating that VECs feeding specific organs are distinct cell types with a stable epigenetic identity. We established universal and lung-specific VEC markers and evaluated their presence in circulating cell-free DNA (cfDNA). Nearly 2.5% of cfDNA in the plasma of healthy individuals originates from VECs. Sepsis, graft versus host disease, and cardiac catheterization are associated with elevated levels of VEC-derived cfDNA, indicative of vascular damage. Lung-specific VEC cfDNA is selectively elevated in patients with chronic obstructive pulmonary disease (COPD) or lung cancer, revealing tissue-specific vascular turnover.Conclusions: VEC cfDNA biomarkers inform vascular dynamics in health and disease, potentially contributing to early diagnosis and monitoring of pathologies, and assessment of drug activity.Funding: This work was supported by the Beutler Research Program, Helmsley Charitable Trust, JDRF, Grail and the DON Foundation (to Y.D.). Y.D holds the Walter & Greta Stiel Chair in heart studies. B.G., R.S., J.M., D.N., T.K., and Y.D. filed patents on cfDNA analysis.