Epigenetic reprogramming and imprinting in origins of disease

Abstract

The traditional view that gene and environment interactions control disease susceptibility can now be expanded to include epigenetic reprogramming as a key determinant of origins of human disease. Currently, epigenetics is defined as heritable changes in gene expression that do not alter DNA sequence but are mitotically and trans-generationally inheritable. Epigenetic reprogramming is the process by which an organism's genotype interacts with the environment to produce its phenotype and provides a framework for explaining individual variations and the uniqueness of cells, tissues, or organs despite identical genetic information. The main epigenetic mediators are histone modification, DNA methylation, and non-coding RNAs. They regulate crucial cellular functions such as genome stability, X-chromosome inactivation, gene imprinting, and reprogramming of non-imprinting genes, and work on developmental plasticity such that exposures to endogenous or exogenous factors during critical periods permanently alter the structure or function of specific organ systems. Developmental epigenetics is believed to establish "adaptive" phenotypes to meet the demands of the later-life environment. Resulting phenotypes that match predicted later-life demands will promote health, while a high degree of mismatch will impede adaptability to later-life challenges and elevate disease risk. The rapid introduction of synthetic chemicals, medical interventions, environmental pollutants, and lifestyle choices, may result in conflict with the programmed adaptive changes made during early development, and explain the alarming increases in some diseases. The recent identification of a significant number of epigenetically regulated genes in various model systems has prepared the field to take on the challenge of characterizing distinct epigenomes related to various diseases. Improvements in human health could then be redirected from curative care to personalized, preventive medicine based, in part, on epigenetic markings etched in the "margins" of one's genetic make-up. NIH Public Access Author ManuscriptRev Endocr Metab Disord. Author manuscript; available in PMC 2014 June 13. Epigenetics meets genetics in disease susceptibilityIn the past, susceptibility of disease was believed to be determined solely by inheritable information carried on the primary sequence of the DNA. Individuals are endowed with different genotypes that dictate how they respond to endogenous factors such as development cues, hormones, and cytokines or to exogenous influences, including nutrient availability, infection, physical activities, social behavior, and other environmental factors. Over time, these responses form the basis of genetic variability to disease susceptibility. Aberrant changes in linear DNA sequence result in mutations, deletions, gene fusion, tandem duplications, or gene amplifications causing dysregulation of gene expression that underlies the genesis of disease [1][2][3][4][5][6][7]. Recently, however, it has become clear that epigenetic disr...

Developmental programming of the metabolic syndrome - critical windows for intervention

“…Histone modifications in conjunction with DNA methylation regulate chromatin structure and gene expression. However, it is still debated where early life and/or environmental factors can influence the "histone" code in a manner similar to their influence on DNA methylation [105] . Adversity during pregnancy or early neonatal life in ex-perimental programming models result in changes in promoter methylation, therefore, directly or indirectly, affect gene expression in pathways associated with a range of physiological processes [106] .…”

“…Therefore, developmental epigenetics is believed to establish 'adaptive phenotypes' to meet the demands of the later-life environment [105,134] . Implicit in this concept is an important process of causality on the cellular level, regulating growth and tissue differentiation and involving chemical changes to the DNA or of associated proteins.…”

“…Once the mechanistic basis of the disease is understood, epigenetic processes are po-tentially reversible and intervention and strategies aimed at reversal could be devised and implemented. However, there are still many key questions to be answered [105] : How plastic is the system for intervention and reversal and what are the critical windows of development at which strategies should be targeted; how many generations does it take to reverse an epigenetic imprint and can surrogate markers be used for disease prediction?…”

The role of early life genistein exposures in modifying breast cancer risk

“…In contrast to mutations or other events that cause alterations in the DNA sequence, epigenetic changes cause alterations in gene transcription; that is they determine whether a gene is expressed or not. Two of the best characterised means of epigenetic modifications are DNA methylation and histone modifications (Tang and Ho, 2007). Epigenetics is now known to be the key process during early development that allows the environment to interact with the genotype, resulting in the observed phenotype.…”

Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver

“…Deaminases convert 5-hydroxymethylcytosine to 5-hydroxymethyluracil which is then repaired to cytosine by the base excision repair pathway (Guo et al, 2011). Methylation of the DNA has been associated with gene silencing, whereas active transcription occurs as a result of demethylation (Franco et al, 2008;Kovatsi et al, 2011;Tang and Ho, 2007).…”