Epigenetics
References 1 Gyparaki et al. DNA methylation biomarkers as diagnostic and prognostic tools in colorectal cancer. J Mol Med (Berl). 2013;91(11):1249-56. 2Toraño et al. The Impact of External Factors on the Epigenome: In Utero and over Lifetime Biomed Res Int. 2016; 2016: 2568635. 3 López et al. The role of 5- hydroxymethylcytosine in development, aging and age- related diseases. Ageing Res Rev. 2017;37:28-38. 4 Raiber et al. Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma. Genomic Medicine 2017;2:6. 5 Johnson, KC, Houseman, EA, King, JE et al. 5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients. Nat Commun. 2016 Nov 25;7:13177.
Differential patterns of DNA methylation are associated with abnormal cellular function and dis- ease, particularly cancers3. The mechanisms responsible for these critical DNA modifications are a key focus in leading-edge drug development. For example, the Ten-Eleven Translocation (TET) family of enzymes converts 5mC to 5hmC in DNA and aberrant TET function is associated with aggressive cancers. Agents that target this pathway may provide the basis of effective oncology thera- pies in the future7.
Power and influence in the epigenome Epigenetic patterns or signatures change through- out our lifetime. Our environment, medicines and even our diets can trigger epigenetic changes that modify and shape our phenotype2. These changes may have a positive physiological or evolutionary impact, allowing us to adapt to our environment, or they may be considered harmful, leading to pro- cesses that make us more vulnerable to disease and affect our well-being.
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Studies involving monozygotic or ‘identical’ twins have provided intriguing insights concerning the genetic and environmental factors that regulate epigenetic pathways or mechanisms, confirming that our genes cannot be wholly responsible for regulating development of complex phenotypic
traits. Identical twins often display disparities in the incidence of conditions such as diabetes, autism and certain types of cancer, despite the inheritance of identical genetic material and consistency of environment during early development9,10. Variability in DNA methylation patterns between monozygotic twins tends to increase with age and become more pronounced in adult twins with divergent medical histories, indicating that lifestyle choices and environmental differences play a con- siderable role in modifying the epigenome9,10. A number of well-characterised epigenetic mod- ifications are highly stable over time and have demonstrated inheritability across generations. Studies in individuals who were prenatally exposed to famine conditions during the Dutch Hunger Winter (1944-45) have revealed shared patterns of DNA methylation within a number of genes asso- ciated with growth and the development of metabolic disease11,12. These modifications dis- rupt normal gene expression and continue to be detected in the same individuals decades later11,12. The impact of these changes on the epidemiology of certain diseases is even evident in subsequent generations; incidence of cardiovascular and metabolic conditions is increased in the children and grandchildren of men and women exposed to the Dutch Hunger Winter13.
Drug Discovery World Fall 2017
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