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Identification of tissue-specific cell death using methylation patterns of circulating DNA
Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-91120 Jerusalem, Israel..
Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-91120 Jerusalem, Israel..
Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-91120 Jerusalem, Israel..
Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-91120 Jerusalem, Israel..
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 13, E1826-E1834 p.Article in journal (Refereed) PublishedText
Abstract [en]

Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic beta-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.

Place, publisher, year, edition, pages
2016. Vol. 113, no 13, E1826-E1834 p.
Keyword [en]
circulating DNA, diagnosis, methylation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-294301DOI: 10.1073/pnas.1519286113ISI: 000372876400010PubMedID: 26976580OAI: oai:DiVA.org:uu-294301DiVA: diva2:929544
Available from: 2016-05-19 Created: 2016-05-18 Last updated: 2016-05-19Bibliographically approved

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Rubertsson, Sten
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Anaesthesiology and Intensive Care
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