A5072583438- Pancreatic function and diabetes
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- Diabetes and associated disorders
- Diabetes Management and Research
- RNA modifications and cancer
- Pancreatic and Hepatic Oncology Research
- SARS-CoV-2 detection and testing
- Congenital heart defects research
- Diet, Metabolism, and Disease
- SARS-CoV-2 and COVID-19 Research
- Biosensors and Analytical Detection
- Eosinophilic Disorders and Syndromes
- Gastrointestinal Tumor Research and Treatment
- Cancer-related gene regulation
- Immunotherapy and Immune Responses
- Cancer, Lipids, and Metabolism
- Lymphoma Diagnosis and Treatment
- Peroxisome Proliferator-Activated Receptors
- Metabolism, Diabetes, and Cancer
- Genetic Syndromes and Imprinting
- Transplantation: Methods and Outcomes
- Apelin-related biomedical research
- Extracellular vesicles in disease
- Genomics and Rare Diseases
Hebrew University of Jerusalem
2005-2025
Hadassah Medical Center
2020-2025
Abstract 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 tissue origins cfDNA, using a reference methylation atlas 25 human tissues and types. The method is validated silico simulations as well vitro mixes from different sources at known proportions. We show that plasma cfDNA healthy donors originates white blood cells (55%), erythrocyte progenitors (30%),...
Significance We describe a blood test for detection of cell death in specific tissues based on two principles: ( i ) dying cells release fragmented DNA to the circulation, and ii each type has unique methylation pattern. have identified tissue-specific markers developed method sensitive these plasma or serum. demonstrate utility identification pancreatic β-cell 1 diabetes, oligodendrocyte relapsing multiple sclerosis, brain patients after traumatic ischemic damage, exocrine pancreas cancer...
Abstract DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing window into cellular identity developmental processes 1 . Current datasets typically include only fraction of sites are often based either on cell lines underwent massive changes in culture or tissues containing unspecified mixtures cells 2–5 Here we describe human methylome atlas, deep whole-genome bisulfite sequencing, allowing fragment-level analysis across...
Detection of cardiomyocyte death is crucial for the diagnosis and treatment heart disease. Here we use comparative methylome analysis to identify genomic loci that are unmethylated specifically in cardiomyocytes, develop these as biomarkers quantify DNA circulating cell-free (cfDNA) derived from dying cells. Plasma healthy individuals contains essentially no cfDNA, consistent with minimal cardiac turnover. Patients acute ST-elevation myocardial infarction show a robust cfDNA signal...
Liver damage is typically inferred from serum measurements of cytoplasmic liver enzymes. DNA molecules released dying hepatocytes are an alternative biomarker, unexplored so far, potentially allowing for quantitative assessment cell death. Here we describe a method detecting acute hepatocyte death, based on quantification circulating, cell-free (cfDNA) fragments carrying hepatocyte-specific methylation patterns. We identified 3 genomic loci that unmethylated specifically in hepatocytes, and...
Pooling multiple swab samples before RNA extraction and real-time reverse transcription polymerase chain reaction (RT-PCR) analysis has been proposed as a strategy to reduce costs increase throughput of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests. However, reports on practical large-scale group testing for SARS-CoV-2 have scant. Key open questions concern reduced sensitivity due sample dilution, the rate false positives, actual efficiency (number tests saved by...
Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death organs affected by cancer be detected tissue-specific methylation patterns of circulating cell-free DNA (cfDNA). We elevated levels hepatocyte-derived cfDNA the plasma patients with liver metastases originating from different primary tumors, compared without metastases. In addition, localized pancreatic or colon showed hepatocyte cfDNA, suggesting inflicted...
How organ size and form are controlled during development is a major question in biology. Blood vessels have been shown to be essential for early of the liver pancreas, fundamental normal pathological tissue growth. Here, we report that, surprisingly, non-nutritional signals from blood act restrain pancreas Elimination endothelial cells increases embryonic pancreatic buds. Conversely, VEGF-induced hypervascularization decreases size. The growth phenotype results vascular restriction tip cell...
Neurogenin3(+) (Ngn3(+)) progenitor cells in the developing pancreas give rise to five endocrine cell types secreting insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. Gastrin is a hormone produced primarily by G-cells stomach, where it functions stimulate acid secretion gastric parietal cells. expressed embryonic common islet tumors, but lineage regulators of gastrin(+) are not known. We report that gastrin abundantly disappears soon after birth. Some co-express ghrelin...
Significance We have studied the dynamics of DNA methylation in pancreatic α- and β-cells reached surprising insights into establishment islet cell identity. Different types share lack cell-type–specific gene promoters, while differences between are concentrated enhancer regions. The findings support fundamental role determining identity, implications for understanding plasticity diabetes.
Blood cell counts often fail to report on immune processes occurring in remote tissues. Here, we use type-specific methylation patterns circulating cell-free DNA (cfDNA) for studying human dynamics. We characterized cfDNA released from specific types healthy individuals (N = 242), cross sectionally and longitudinally. Immune levels had no individual steady state as opposed blood counts, suggesting that concentration reflects adjustment of survival maintain homeostatic numbers. also observed...
Assessment of pancreas cell type composition is crucial to the understanding genesis diabetes. Current approaches use immunodetection protein markers, for example, insulin as a marker β-cells. A major limitation these methods that content varies in physiological and pathological conditions, complicating extrapolation actual number. Here, we demonstrate type–specific DNA methylation markers determining fraction specific types human islet specimens. We identified genomic loci are uniquely...
Allele-specific DNA methylation reflects genetic variation and parentally-inherited changes, is involved in gene regulation pathologies. Yet, our knowledge of this phenomenon largely limited to blood. Here we present a comprehensive atlas allele-specific using deep whole-genome sequencing across 39 normal human cell types. We identified 325k regions, covering 6% the genome 11% CpGs, that show bimodal distribution methylated unmethylated molecules. In 34k these variations at individual...
Type 1 diabetes is an incurable disease that currently treated by insulin injections or in rare cases islet transplantation. We have recently shown NKp46, a major killer receptor expressed NK cells, recognizes unknown ligand β cells and the absence of when its activity blocked, development inhibited. In this study, we investigate whether NKp46 involved killing human are intended to be used for transplantation, also thoroughly characterize interaction between mouse cell ligands. show express...
Microsomal triglyceride transfer protein (MTP) catalyzes the assembly of (TG)-rich apolipoprotein B-containing liver (e.g., VLDL) and intestinal chylomicron) lipoproteins. The human MTP gene promoter is reported here to associate in vivo with endogenous hepatocyte nuclear factor-4α (HNF-4α) be transactivated or transsuppressed by overexpressed dominant negative HNF-4α, respectively. Human (hMTP) transactivation HNF-4α accounted for concerted activity distal (−83/−70) proximal (−50/−38)...
Abstract Pooling multiple swab samples prior to RNA extraction and RT-PCR analysis was proposed as a strategy reduce costs increase throughput of SARS-CoV-2 tests. However, reports on practical large-scale group testing for have been scant. Key open questions concern reduced sensitivity due sample dilution; the rate false positives; actual efficiency (number tests saved by pooling) impact infection in population assay performance. Here we report 133,816 collected at April-September 2020,...
Abstract DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 types sorted from 207 healthy tissue samples. Replicates the same cell-type are >99.5% identical, demonstrating robustness identity programs to genetic variation environmental perturbation....