Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease.
Joshua MossJudith MagenheimDaniel NeimanHai ZemmourNetanel LoyferAmit KorachYaacov SametMyriam MaozHenrik DruidPeter ArnerKeng-Yeh FuEndre KissKirsty L SpaldingGiora LandesbergAviad ZickAlbert GrinshpunA M James ShapiroMarkus GrompeAvigail Dreazan WittenbergBenjamin GlaserRuth ShemerTommy KaplanYuval DorPublished in: Nature communications (2018)
Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.
Keyphrases
- endothelial cells
- cell death
- single cell
- prostate cancer
- dna methylation
- papillary thyroid
- end stage renal disease
- induced pluripotent stem cells
- high glucose
- public health
- pluripotent stem cells
- induced apoptosis
- gene expression
- intensive care unit
- acute kidney injury
- newly diagnosed
- chronic kidney disease
- mesenchymal stem cells
- young adults
- stem cells
- squamous cell carcinoma
- minimally invasive
- molecular dynamics
- molecular docking
- health information
- drinking water
- lymph node
- risk assessment
- childhood cancer
- radiation therapy
- bone marrow
- signaling pathway
- peritoneal dialysis
- solid phase extraction
- molecularly imprinted
- climate change