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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The last decade has seen a growing awareness of epigenetic disregulations associated with cancer and other diseases. In the future, the measurement of epigenetic changes may represent an ideal diagnostic tool and could also provide targets for new therapies. Clinicians predict that epigenetic tests will be incorporated into most cancer treatment strategies in the coming years for the early detection, prognosis, and prediction of therapeutic response. However, there is also recognition that current epigenetic clinical tests are based mainly on individual genes or small panels of genes which may not have sufficient statistical representation to provide accurate results given the heterogeneity in genetic and epigenetic alterations in tumor cells both within and between individual patients. However, a factor facilitating the introduction of epigenomic technologies is the declining cost of genomic sequencing. Also, the Human Epigenome Project (HEP) is a multinational science project, with the stated aim of identifying, cataloguing, and interpreting genome-wide DNA methylation patterns of all human genes in all major tissues. It is financed by government funds and private investment via a consortium of genetic research organizations including the Wellcome Trust Sanger Institute (UK), Epigenomics AG (Germany/US), and the Centre National de Génotypage (France). Eventually, a comprehensive epigenomic map will be obtained that should be valuable in predicting the risk for certain diseases including cancer, and suggesting risk-lowering lifestyle changes that could be made for individuals.
Beckwith–Wiedemann Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Jirat Chenbhanich, Sirisak Chanprasert, Wisit Cheungpasitporn
Of the approximately 100 imprinted genes known to date, most are clustered together, with each cluster containing 2–15 genes and varying in size from <100 kb to several megabases [6]. The establishment of imprints—“the imprinting cycle”—is sophisticated and needs to be reset at each generation [8]. The expression of genes in the imprinting cluster is controlled by discreet DNA segments called imprinting control region (ICR). In the primordial germ cells, human epigenome undergoes extensive reprogramming, where global erasure of DNA methylation occurs and parent-specific imprints are removed. During gametogenesis, ICRs are differentially methylated in either paternal or maternal germline. Following fertilization, these marked regions are robustly protected against a wave of genome-wide demethylation and subsequent de novo methylation. These differentially methylated regions later regulate the paternally or maternally expressed alleles of many genes in the same region during human development. Dysregulation of imprinting will result in imprinting disorders, of which the most well-known are 15q11-13-associated Prader–Willi syndrome and Angelman syndrome, and 11p15.5-associated BWS and Silver−Russell syndrome.
Developmental plasticity, epigenetic mechanisms and early life influences on adult health and disease: Fundamental concepts
Published in Nicholas C. Harvey, Cyrus Cooper, Osteoporosis: a lifecourse epidemiology approach to skeletal health, 2018
Elizabeth M Curtis, Karen Lillycrop, Mark Hanson
Studies in animal models, where the diet pre- and post-pregnancy as well as genetic background can be carefully controlled, have been instrumental in demonstrating long-term effects of nutrition on the epigeneome. Evidence that maternal diet in humans can induce long-term epigenetic and phenotypic changes in the offspring is more limited. However, in humans, alterations have been reported in the methylation of a number of genes in DNA isolated from whole blood from individuals whose mothers were exposed to famine during the Dutch Hunger Winter. The timing of the nutritional constraint appeared to be important, as exposure to famine around the time of conception was associated with a small decrease in CpG methylation of the imprinted IGF2 gene and an increase in methylation of leptin, IL-10, MEG3 and ABCA4 (50), while late gestation famine exposure had no effect on methylation. This study also provided evidence that maternal nutritional constraint induces long-term epigenetic changes in key metabolic regulatory genes, as these measurements were made 60 years after the famine exposure. Studies of dietary supplementation with 400μg of folic acid per day around the time of conception have also shown altered methylation of specific CpG sites in the IGF2 gene in the peripheral blood cells of children (51). There is also some evidence that plasticity in the human epigenome may persist into adulthood, as, for example, short-term high fat overfeeding in healthy young men was shown to induce methylation changes in over 6000 skeletal muscle genes, with only partial reversal after 6 to 8 weeks of a normocaloric diet (52).
It starts from the womb: maximizing bone health
Published in Climacteric, 2022
R. F. Vasanwala, L. Gani, S. B. Ang
These DNA-sequence variants form the template upon which environmental factors can influence the phenotype, by a number of mechanisms, including the epigenetic markers [118]. Epigenetic mechanisms include information-containing factors, other than the DNA sequence, that cause stable changes in gene expression and are maintained during cell divisions [119]. It is thought that epigenetic programming plays a major role in mediating the effects of factors such as maternal nutrition and vitamin D status. However, the exact role of epigenetic factors in relation to prenatal exposures and skeletal disease has not yet been elucidated. In addition, epigenetic programming and plasticity continue throughout adult life. Variance in epigenetic markers increases with age, which is thought to reflect responses to environmental exposures that modulate gene expression [118]. A number of epigenome-wide association studies have been conducted to examine association with osteoporosis. However, results have been variable as bone is a multicellular tissue and methylation differences accounting for changes in cell-type proportion were not accounted for in some of the published studies. It is hoped that, through continued advances in epigenomic mechanism studies with collaborative efforts, a clearer map of the human epigenome and skeletal health will be unraveled.
Epigenetics, nutrition and mental health. Is there a relationship?
Published in Nutritional Neuroscience, 2018
Aaron J. Stevens, Julia J. Rucklidge, Martin A. Kennedy
Many human diseases are influenced by the interaction between genetic and environmental factors.3,69,216–218 Therefore, understanding how genes respond to our environment is central to managing health and disease, and is one of the major contemporary challenges in genetics.70,219,220 While we have clear evidence of the impacts of smoking on methylation marks,213,221,222 and dietary impacts in mice,5 we know very little about dietary effects on the human epigenome. DNA methylation is an important process for modulating both physical and mental development, and several associations have been observed between methylation and human disease. The effect of DNA methylation on gene expression is potentially reversible which makes it a possible target for therapeutic intervention. It has been shown that methylation pathways are regulated by dietary factors, including micronutrients, which encourages further examination of whether targeted dietary supplementation can be used to control or modulate epigenetically directed disease risk.
Epigenetic regulatory modifications in genetic and sporadic frontotemporal dementia
Published in Expert Review of Neurotherapeutics, 2018
Chiara Fenoglio, Elio Scarpini, Daniela Galimberti
DNA methylation is the most characterized epigenetic modification that involves the addition of a methyl group to the carbon-5 of a cytosine residue in DNA and is carried out by one of the several DNA methyltransferase (DNMT) enzymes. DNMT1 is the enzyme responsible for the maintenance of DNA methylation patterns during DNA replication. DNMT1 localizes to the DNA replication fork, where it methylates nascent DNA strands at the same locations as in the template strand [10]. DNMT3a and DNMT3b are involved in the de novo methylation of unmethylated and hemimethylated sites in nuclear and mitochondrial DNA, respectively [10,11]. In mammals, DNA methylation occurs predominantly at CpG sites where a cytosine nucleotide is followed by a guanine nucleotide. CpG sites can occur in concentrations of up to several hundred dinucleotide repeats, called CpG islands, which are frequently found in gene promoter regions. The methylation or hypermethylation of CpG islands in promoter regions usually prevents the expression of the associated gene [12]. DNA methylation is known to have a crucial role in normal development, cell proliferation, and genome stability [13]. However, non-CpG methylation has also received increased attention [14]. The design and development of techniques for the identification, quantification, and positioning of individual CpG methylation across the genome is a milestone that needs to be accomplished in order to provide a reliable characterization of the human epigenome.