Methylome

Detection of cardiomyocyte death is crucial for the diagnosis and treatment of heart disease. Here we use comparative methylome analysis to identify genomic loci that are unmethylated specifically in cardiomyocytes, and develop these as biomarkers to quantify cardiomyocyte DNA in circulating cell-free DNA (cfDNA) derived from dying cells. Plasma of healthy individuals contains essentially no cardiomyocyte cfDNA, consistent with minimal cardiac turnover. Patients with acute ST-elevation myocardial infarction show a robust cardiac cfDNA signal that correlates with levels of troponin and creatine phosphokinase (CPK), including the expected elevation-decay dynamics following coronary angioplasty...

SCOPE: The enzyme nicotinamide N-methyltransferase (NNMT) is a major methyltransferase in adipose tissue. We hypothesized an epigenetic signature in association with NNMT gene expression in adipose tissue. METHODS AND RESULTS: The global human methylome was analyzed in visceral adipose tissue (VAT) from morbidly obese patients using the Infinium HumanMethylation450 BeadChip array (discovery cohort: n  =  11). The findings were confirmed in two additional independent cohorts (Cohort 1: n  =  60; BMI 20-60 kg/m2 and cohort 2: n  =  40; BMI >40 kg/m2 ) and validated after weight loss (using microarray data)...

BACKGROUND: The characterization of genomic or epigenomic variation in human and animal models could provide important insight into pathophysiological mechanisms of various diseases, and lead to new developments in disease diagnosis and clinical intervention. The African green monkey (AGM; Chlorocebus aethiops) and cynomolgus monkey (CM; Macaca fascicularis) have long been considered important animal models in biomedical research. However, non-human primate-specific methods applicable to epigenomic analyses in AGM and CM are lacking...

DNA methylation (DNAm) clocks such as the Horvath DNAm clock provide the most accurate biological determination of biological age relative to chronological age available today. However, there is little correlation between DNAm clocks, telomere-based aging clocks, and transcriptomic-based aging clocks. Recently, a genome-wide association study identified single-nucleotide polymorphism variants of TERT, the gene that encodes telomerase, as accelerating intrinsic aging in the Horvath DNAm clock. These same variants have been previously associated with long telomeres in leukocytes, suggesting that TERT acts paradoxically on telomere-associated aging and DNAm-associated aging...

Phthalates are known endocrine disruptors and associated with decreased fecundity, pregnancy loss, and adverse obstetrical outcomes, however the underlying mechanisms remain to be established. Environmental factors can influence gene expression and cell function by modifying epigenetic marks, impacting the developing embryo as well as future generations of offspring. The impact of phthalates on placental gene methylation and expression is largely unknown. We studied the effect of maternal phthalate exposure on the human placental DNA methylome and transcriptome...

Altered epigenetic regulation is central to many human diseases, including cancer. Over the past two decade, major advances have been made in our understanding of the role of epigenetic alterations in carcinogenesis, particularly for DNA methylation, histone modifications and non-coding RNAs. Aberrant hypermethylation of DNA at CpG islands is a well-established phenomenon that mediates transcriptional silencing of tumor suppressor genes, and it is an early event integral to gastrointestinal cancer development...

Alterations of DNA methylation landscapes and machinery are a hallmark of many human diseases. A prominent case is the ICF syndrome, a rare autosomal recessive immunological/neurological disorder diagnosed by the loss of DNA methylation at (peri)centromeric repeats and its associated chromosomal instability. It is caused by mutations in the de novo DNA methyltransferase DNMT3B in about half of the patients (ICF1). In the remainder, the striking identification of mutations in factors devoid of DNA methyltransferase activity, ZBTB24 (ICF2), CDCA7 (ICF3) or HELLS (ICF4), raised key questions about common or distinguishing DNA methylation alterations downstream of these mutations and hence, about the functional link between the four factors...

DNA methylation on N6 -adenine (6mA) has recently been found to be a potentially epigenetic mark in several unicellular and multicellular eukaryotes. However, its distribution patterns and potential functions in land plants, which are primary producers for most ecosystems, remain largely unknown. Here we report global profiling of 6mA sites at single-nucleotide resolution in the genome of Arabidopsis thaliana at different developmental stages using single-molecule real-time sequencing. 6mA sites are widely distributed across the Arabidopsis genome and enriched over the pericentromeric heterochromatin regions...

The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Using whole-genome bisulfite sequencing, we show for the first time that cancer-associated fibroblasts (CAFs) from localized prostate cancer display remarkably distinct and enduring genome-wide changes in DNA methylation, significantly at enhancers and promoters, compared to nonmalignant prostate fibroblasts (NPFs)...

Background: The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT→TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population. Patients and Methods: ARTE was a 2:1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg x 14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years...

Short-term exposures at critical stages of development can lead to delayed adverse effects long after the initial stressor has been removed, a concept referred to as developmental origin of adult disease. This indicates that organisms' phenotypes may epigenetically reflect their past exposure history as well as reflecting chemicals currently present in their environment. This concept has significant implications for environmental monitoring. However, there is as yet little or no implementation of epigenetics in environmental risk assessment...

DNA methylation is mediated by a conserved family of DNA methyltransferases (Dnmts). The human genome encodes three active Dnmts (Dnmt1, Dnmt3a and Dnmt3b), the tRNA methyltransferase Dnmt2, and the regulatory protein Dnmt3L. Despite their high degree of conservation among different species, genes encoding Dnmts have been duplicated and/or lost in multiple lineages throughout evolution, indicating that the DNA methylation machinery has some potential to undergo evolutionary change. However, little is known about the extent to which this machinery, or the methylome, varies among vertebrates...

DNA methylation is a chromatin modification that can provide epigenetic regulation of gene and transposon expression. Plants utilize several pathways to establish and maintain DNA methylation in specific sequence contexts. The chromomethylase (CMT) genes maintain CHG (where H = A, C or T) methylation. The RNA-directed DNA methylation (RdDM) pathway is important for CHH methylation. Transcriptome analysis was performed in a collection of Zea mays lines carrying mutant alleles for CMT or RdDM-associated genes...

5-methylcytosine (5mC) is the best understood DNA modification and is generally believed to be associated with repression of gene expression. Over the last decade, sequentially oxidized forms of 5mC (oxi-mCs) have been discovered within the genomes of vertebrates. Their discovery was accompanied by that of the ten-eleven translocation (TET) methylcytosine dioxygenases, the enzymes that catalyze the formation of the oxi-mCs. Although a number of studies performed on different vertebrate models and embryonic stem cells demonstrated that both TET enzymes and oxi-mCs are likely to be important for several developmental processes it is currently unclear whether their developmental roles are conserved among vertebrates...

BACKGROUND: In recent years, epigenetics has gained a central role in the understanding of the process of natural selection. It is now clear how environmental impacts on the methylome could promote methylation variability with direct effects on disease etiology as well as phenotypic and genotypic variations in evolutionary processes. To identify possible factors influencing inter-individual methylation variability, we studied methylation values standard deviation of 166 healthy individuals searching for possible associations with genomic features and evolutionary signatures...

NOMe-seq (nucleosome occupancy and methylome sequencing) identifies nucleosome-depleted regions that correspond to promoters, enhancers, and insulators. The NOMe-seq method is based on the treatment of chromatin with the M.CviPI methyltransferase, which methylates GpC dinucleotides that are not protected by nucleosomes or other proteins that are tightly bound to the chromatin (GpCm does not occur in the human genome and therefore there is no endogenous background of GpCm ). Following bisulfite treatment of the M...

DNA methylation is a dynamic epigenetic mark that characterizes different cellular developmental stages, including tissue-specific profiles. This CpG dinucleotide modification cooperates in the regulation of the output of the cellular genetic content, in both healthy and pathological conditions. According to endogenous and exogenous stimuli, DNA methylation is involved in gene transcription, alternative splicing, imprinting, X-chromosome inactivation, and control of transposable elements. When these dinucleotides are organized in dense regions are called CpG islands (CGIs), being commonly known as transcriptional regulatory regions frequently associated with the promoter region of several genes...

Maternal exposure to airborne particulate matter (PM) has been associated with restricted foetal growth and reduced birthweight. Here, we performed methylome-wide analyses of cord and children's blood DNA in relation to residential exposure to PM smaller than 10µm (PM10). This study included participants of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC, cord blood, n=780; blood at age 7, n=757 and age 15-17, n=850) and the EXPOsOMICS birth cohort consortium including cord blood from ENVIRONAGE (n=197), INMA (n=84), Piccolipiù (n=99) and Rhea (n=75)...

BACKGROUND: Offspring exposed to gestational diabetes mellitus (GDM) are at a high risk for metabolic diseases. The mechanisms behind the association between offspring exposed to GDM in utero and an increased risk of health consequences later in life remain unclear. The aim of this study was to clarify the changes in methylation levels in the foetuses of women with GDM and to explore the possible mechanisms linking maternal GDM with a high risk of metabolic diseases in offspring later in life...

The faithful inheritance of the epigenome is critical for cells to maintain gene expression programs and cellular identity across cell divisions. We mapped strand-specific DNA methylation after replication forks and show maintenance of the vast majority of the DNA methylome within 20 minutes of replication and inheritance of some hemimethylated CpG dinucleotides (hemiCpGs). Mapping the nascent DNA methylome targeted by each of the three DNA methyltransferases (DNMTs) reveals interactions between DNMTs and substrate daughter cytosines en route to maintenance methylation or hemimethylation...