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 transgenerationally 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.

Fig. 1

Schematic diagram of our hypothesis on how neonatal estrogen (E2) and bisphenol A (BPA) alter the prostate genome via DNA methylation and histone modifications with phosphodiesterase type 4 variant 4 (PDE4D4) used as an example. Without exposure to E2 and BPA, PDE4D4 is silenced with aging. A group of enzymes, including histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and methylated DNA-binding protein (MeCP2), may be involved in gene silencing. Nevertheless, after exposure to E2 and BPA, PDE4D4 fails to “shut-off” and is actively transcribed throughout life. We propose that chromatin structure is remodeled by opening the chromatin in the presence of histone acetyltransferase (HAT), methylation binding domains (MBDs) and other unknown factors and that this remodeling further prevents HDACs, DNMTs, and MeCP2 from binding to silence the gene. Persistent elevation of PDE4D4 expression is associated with the increase in incidence of prostate cancer later in life