The DNA methylome of human vascular endothelium and its use in liquid biopsies

Ayelet Peretz, Netanel Loyfer, Sheina Piyanzin, Bracha Lea Ochana, Daniel Neiman, Judith Magenheim, Agnes Klochendler, Zeina Drawshy, Ilana Fox-Fisher, Ori Fridlich, Joshua Moss, Daniel Cohen, Hai Zemmour, Gordon Cann, Joerg Bredno, Oliver Venn, Batia Avni, Tural Alekberli, Yaacov Samet, Amit KorachOri Wald, Vladimir Yutkin, Uzi Izhar, Nir Pillar, Markus Grompe, Zvi Fridlender, Ariel Rokach, David Planer, Giora Landesberg, Benjamin Glaser, Ruth Shemer, Tommy Kaplan, Yuval Dor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)263-281.e4
JournalMed
Volume4
Issue number4
DOIs
StatePublished - 14 Apr 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • DNA methylation
  • Translation to patients
  • biomarkers
  • cfDNA
  • liquid biopsy
  • tissue dynamics
  • vascular endothelial cells

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