A5015927678- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- Genetic Syndromes and Imprinting
- RNA modifications and cancer
- Pancreatic function and diabetes
- Prenatal Screening and Diagnostics
- Cancer-related gene regulation
- Diabetes and associated disorders
- Pancreatic and Hepatic Oncology Research
- Genetics and Neurodevelopmental Disorders
- Diabetes Management and Research
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Genomics and Chromatin Dynamics
- Genetic factors in colorectal cancer
- Organ Transplantation Techniques and Outcomes
- Single-cell and spatial transcriptomics
- Renal cell carcinoma treatment
- Brain Metastases and Treatment
- Vitamin C and Antioxidants Research
- Glioma Diagnosis and Treatment
- Blood groups and transfusion
- Pharmacological Effects of Natural Compounds
- Cancer-related molecular mechanisms research
- Blood donation and transfusion practices
- Extracellular vesicles in disease
Hadassah Medical Center
1984-2025
Hebrew University of Jerusalem
2010-2025
Debre Berhan University
2024
Association for Symbolic Logic
2023
City of Hope
1997-2009
Beckman Research Institute
1997-2009
Hebrew College
2005
Israel Oceanographic and Limnological Research
2000
Technion – Israel Institute of Technology
2000
University Medical Center
1984
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%),...
Methylation patterns of specific genes have been studied by polymerase chain reaction and found to undergo dynamic changes in the germ line early embryo. Some CpG sites are methylated sperm DNA unmodified mature oocytes, indicating that parental genomes differential methylation profiles. These differences, however, erased a series embryonic demethylation postblastula remodification events, which serve reestablish basic adult pattern prior organogenesis. During gametogenesis, all these...
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...
The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, its ability to natively profile DNA methylation without complex sample processing is attractive for point-of-care real-time sequencing. We recently demonstrated ONT shallow whole-genome sequencing detect copy number alterations (CNAs) from the circulating tumor (ctDNA) of cancer patients. Here, we show that cell type cancer-specific changes can also be detected, as well cancer-associated fragmentation...
The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly in patients with atherosclerosis, more than 10% experiencing events1,2. However, the enormous medical burden this clinical phenomenon, underlying mechanisms leading to increased vascular and are largely unknown. Here, using a novel mouse model stroke-induced ischaemia, we show that leads activation AIM2 inflammasome vulnerable atherosclerotic...
The mouse Snrpn gene encodes the Smn protein, which is involved in RNA splicing. maps to a region central part of chromosome 7 that syntenic Prader–Willi/Angelman syndromes (PWS-AS) on human 15q11-q13. gene, like its counterpart, imprinted and paternally expressed, primarily brain heart. We provide here detailed description structural features differential methylation pattern gene. have identified maternally methylated at 5′ end (DMR1), correlates inversely with paternal expression. also...
The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent activate an islet β cell program, we performed in vivo screen by expressing three "reprogramming factors" wide spectrum tissues. We report that transient intestinal expression these factors-Pdx1, MafA, and Ngn3 (PMN)-promotes rapid conversion crypt into endocrine...
The pattern of methylation mouse mitochondrial DNA (mtDNA) was studied using several techniques. By employing a sensitive analytical procedure it possible to show that this contains the modified base 5-methylcytosine (m5Cyt). This residue occurred exclusively at dinucleo-tide sequence CpG frequency 3 5%. further investigated by determining state MspI(HpaII) sites. Different sites were found be methylated different extent, implying mtDNA is nonrandom. Based on known composition and nucleotide...
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...
Tumor-derived circulating cell-free DNA (cfDNA) is present in the plasma of individuals with cancer. Assays aimed at detecting common cancer mutations cfDNA are being developed for detection several types. In breast cancer, however, such assays have failed to detect disease a sensitivity relevant clinical use, part due absence multiple that can be co-detected plasma. Unlike individual exist only subset tumors, unique methylation patterns universally cells type and therefore may ideal...
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...
Strenuous physical exercise causes a massive elevation in the concentration of circulating cell-free DNA (cfDNA), which correlates with effort intensity and duration. The cellular sources physiological drivers this phenomenon are unknown. Using methylation patterns cfDNA associated histones, we show that originates mostly extramedullary polymorphonuclear neutrophils. Strikingly, cardiomyocyte increases after marathon, consistent elevated troponin levels indicating low-level, delayed cardiac...
AbstractDisruptions in the expression of Bdnf gene that encodes a neurotrophic factor involved neuronal survival, differentiation and synaptic plasticity has been proposed to contribute molecular pathogenesis Rett syndrome. syndrome (RTT) is neurodevelopmental disorder, caused by mutations X-linked methyl CpG binding protein 2 (MeCP2). MeCP2 deficiency brain shown decrease overall spite an observed increase activity promoter III appears be controlled directly MeCP2. Therefore, how causes...
Rett syndrome (RS) is a severe and progressive neurodevelopmental disorder caused by heterozygous mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. MeCP2 nuclear that binds specifically to methylated DNA functions as general transcription repressor context of chromatin remodeling complexes. RS shares clinical features with those Angelman (AS), an imprinting disorder. In AS patients, maternally expressed copy UBE3A codes for ubiquitin ligase 3A (E6-AP) repressed. The...
Objective Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed. Design To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among cases patients with chronic pancreatitis, colorectal cancer (CRC), healthy controls. Using CA19-9 as anchor marker, measurements...
Chronological age prediction from DNA methylation sheds light on human aging, health, and lifespan. Current clocks are mostly based linear models rely upon hundreds of sites across the genome. Here, we present GP-age, an epigenetic non-linear cohort-based clock for blood, 11,910 methylomes. Using 30 CpG alone, GP-age outperforms state-of-the-art models, with a median accuracy ∼2 years held-out blood samples, both array sequencing-based data. We show that aging-related changes occur at...
The polycomb repressive complex (PRC) 1 protein Ring1B is an ubiquitin ligase that modifies nucleosomal histone H2A, a modification which plays critical role in regulation of gene expression. We have shown self-ubiquitination generates multiply branched, "noncanonical" polyubiquitin chains do not target the for degradation, but rather stimulate its activity toward H2A. This finding implies targeted by heterologous E3. In this study, we identified E6-AP (E6-associated protein) as targets...
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.