Monitoring liver damage using hepatocyte-specific methylation markers in cell-free circulating DNA
| Autor: | Ruth Shemer, Daniel Neiman, Hai Zemmour, Markus Grompe, Kim M. Olthoff, Benjamin Glaser, Judith Magenheim, Ofri Abraham, Sheina Piyanzin, Giora Landesberg, Roni Lehmann-Werman, Joshua Moss, Bao Li Loza, Ilana Fox, Talya Dor, Yuval Dor, Abraham Shaked |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty medicine.medical_treatment Bisulfite sequencing Proteinase Inhibitory Proteins Secretory Liver transplantation Sensitivity and Specificity Receptor IGF Type 2 03 medical and health sciences Internal medicine Hepatectomy Humans Medicine Aspartate Aminotransferases Epigenetics Glycoproteins Cell Death business.industry Liver Diseases Liver cell High-Throughput Nucleotide Sequencing Alanine Transaminase Blood Proteins General Medicine DNA Methylation Hepatology Molecular biology Liver Transplantation 3. Good health Transplantation 030104 developmental biology medicine.anatomical_structure Liver Technical Advance Hepatocyte Toxicity Hepatocytes business Cell-Free Nucleic Acids Biomarkers |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.120687 |
| Popis: | Liver damage is typically inferred from serum measurements of cytoplasmic liver enzymes. DNA molecules released from dying hepatocytes are an alternative biomarker, unexplored so far, potentially allowing for quantitative assessment of liver cell death. Here we describe a method for detecting acute hepatocyte death, based on quantification of circulating, cell-free DNA (cfDNA) fragments carrying hepatocyte-specific methylation patterns. We identified 3 genomic loci that are unmethylated specifically in hepatocytes, and used bisulfite conversion, PCR, and massively parallel sequencing to quantify the concentration of hepatocyte-derived DNA in mixed samples. Healthy donors had, on average, 30 hepatocyte genomes/ml plasma, reflective of basal cell turnover in the liver. We identified elevations of hepatocyte cfDNA in patients shortly after liver transplantation, during acute rejection of an established liver transplant, and also in healthy individuals after partial hepatectomy. Furthermore, patients with sepsis had high levels of hepatocyte cfDNA, which correlated with levels of liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Duchenne muscular dystrophy patients, in which elevated AST and ALT derive from damaged muscle rather than liver, did not have elevated hepatocyte cfDNA. We conclude that measurements of hepatocyte-derived cfDNA can provide specific and sensitive information on hepatocyte death, for monitoring human liver dynamics, disease, and toxicity. |
| Databáze: | OpenAIRE |
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