Medical epigenetics最新文献

During fetal development and early-infancy, environmental signals can induce epigenetic changes that alter neurobehavioral development and later-life mental health. Several neurodevelopmental genetic diseases influence epigenetic regulatory genes and genomic imprinting. Recently, brain epigenetic marks have been involved in idiopathic neurodevelopmental disorders including autism spectrum disorders (ASD). The placenta is an important regulator of the intrauterine environment that links maternal and fetal nervous systems. Placental epigenetic signatures have been associated with neurodevelopment of healthy newborns quantified through the NICU Network Neurobehavioral Scales (NNNS). Associations have been observed for DNA methylation of genes involved in cortisol (NR3C1, HSD11B), serotonin (HTR2A), and metabolic (LEP) pathways. Dysregulation of imprinted genes and microRNAs has also been associated with neurobehavior assessed by NNNS. Further analysis is needed to characterize the mechanisms by which the epigenome influences neurodevelopment, and the connection between this dysregulation and mental health disorders. In the future, epigenetic marks could serve as functional biomarkers of mental health and cognitive function.

Genome-wide association studies (GWAS) have become a powerful tool in the identification of disease-associated variants. Unfortunately, many of these studies have found that the estimated variability in cardiovascular disease risk cannot be fully explained by traditional paradigms of genetic variation in protein coding genes. Moreover, traditional views do not sufficiently explain the well-known link between cardiovascular disease and environmental influence. We posit that epigenetics, defined as chromatin-based mechanisms important in the regulation of gene expression that do not involve changes in the DNA sequence per se, represents the missing link. The nuclear-based mechanisms that contribute to epigenetic gene regulation can be broadly separated into three unique but highly interrelated processes: DNA methylation and hydroxymethylation; histone density and post-translational modifications; and RNA-based mechanisms. Together they complement the cis/trans perspective on transcriptional control paradigms in blood vessels. Moreover, it provides a molecular basis for understanding how the environment impacts the genome to modify cardiovascular disease risk over the lifetime of a cell and its offspring. This review provides an introduction to epigenetic function and cardiovascular disease, with a focus on endothelial cell biology. Additionally, we highlight emerging concepts on epigenetic gene regulation that are highly relevant to atherosclerosis and coronary artery disease.

Introduction: Bisulfite treatment of DNA introduces methylation-dependent sequence changes through selective chemical conversion of nonmethylated cytosine to uracil and serves as pretreatment step for the majority of DNA methylation analysis methods.

Methods: We have evaluated the conversion performance of five of the most commonly used bisulfite treatment kits [MethylDetector (Active Motif), Epitect+ (Qiagen), Zymo Methylation, Zymo Gold and Zymo Lightning (all from Zymo Research)] by pyrosequencing four different regions with variable methylation levels, including: a repetitive element (ALUSX), a gene with low levels of methylation (IL6ST), an imprinted gene expected to be approximately 50% methylated (IGF2), and a fully methylated gene (ST3GAL2). In addition, we have studied the influence of duration (3 vs. 16 h) and type (fixed temperature vs. cycling program) of incubation protocol on the conversion efficiency of each evaluated kit.

Results: All kits produced similar conversion rates of ALUSX, IGF2 and ST3GAL2, while the conversion of the low methylated IL6ST gene was variable between kits. The Zymo kits were highly consistent in their performance even when different protocols of incubation were applied, generating full conversion at the low methylated gene IL6; this was not true for the MethylDetector and Epitect+ kits. However, long-cycling incubation could produce similar conversion rates for the same locus in combination with Active Motif and Qiagen kits.

Conclusions: The selection of a long-cycling protocol during conversion permits standardization of protocols, improving the reproducibility of methylation estimates across laboratories for gene-specific, genome-wide and bisulfite-based sequencing analyses.

Increasing evidence suggest that epigenetic alterations can greatly impact human health, and that epigenetic mechanisms (DNA methylation, histone modifications, and microRNAs) may be particularly relevant in responding to environmental toxicant exposure early in life. The epigenome plays a vital role in embryonic development, tissue differentiation and disease development by controlling gene expression. In this review we discuss what is currently known about epigenetic alterations in response to prenatal exposure to inorganic arsenic (iAs) and lead (Pb), focusing specifically on their effects on DNA methylation. We then describe how epigenetic alterations are being studied in newborns as potential biomarkers of in utero environmental toxicant exposure, and the benefits and challenges of this approach. In summary, the studies highlighted herein indicate how epigenetic mechanisms are impacted by early life exposure to iAs and Pb, and the research that is being done to move towards understanding the relationships between toxicant-induced epigenetic alterations and disease development. Although much remains unknown, several groups are working to understand the correlative and causal effects of early life toxic metal exposure on epigenetic changes and how these changes may result in later development of disease.