DILEMMAS WITH EPIGENETICS
ABNORMAL EPIGENETIC EFFECTS
CANCER RISK
It is now widely accepted that epigenetics plays a key role in many cancers. Two types of abnormal DNA methylation patterns are observed in virtually all human cancers, including colon, breast, prostate, and lung tumors. This loss of methylation could result in the activation of normally suppressed oncogenes, which are genes that promote tumor formation, thereby increasing the risk of cancer. The overall reduction of methylation in cancerous cells is accompanied by increases in methylation (hypermethylation) at specific sites in the genome. Another epigenetic mechanism of cancer causation is a loss of imprinting. Activation of the normally silent copy of an imprinted growth-promoting gene, or aberrant silencing of the normally expressed copy of an imprinted tumor suppressor gene, can result in cancer formation.
TRANSGENERATIONAL EFFECTS
Maternal exposure to hormone-disrupting chemicals (or endocrine disruptors), such as xenoestrogens, oestrogenic (estrogenic), and hormone-mimicking chemicals, may interfere with the epigenetic reprogramming of the fetal germline at key stages of early development, resulting in transgenerational adverse effects. Animal tests suggest the effects of maternal exposure were transmitted through the maternal germline to offspring via both genetic and epigenetic mechanisms. Endocrine disruptor chemicals may operate through epigenetic mechanisms to adversely affect human health. These mechanisms can induce a wide variety of adverse effects, including spermatogenic abnormalities, male infertility, breast cancer, and kidney disease, in animal tests, not only in the first generation but also in generations two through four. These abnormalities occur at frequencies ranging from twenty to ninety percent of individual animals in subsequent generations, an enormously high rate that is consistent with an epigenetic mechanism.
DRUG RESISTANCE
Chemotherapy resistance remains an important problem in cancer. The acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA-binding proteins (RBPs) and miRNAs, which change the stability and translation of mRNA encoding factors involved in cell survival, proliferation, epithelial-mesenchymal transition, and drug metabolism. Alterations mediated by epigenetic mechanisms are important factors in cancer progression and in response to treatment in different types of cancer. Alterations in chromatin acetylation and DNA double-strand breaks (DSBs) in oral lichen planus (OLP) are accompanied by different responses to therapy.
EPIGENETIC BENEFITS
ALZHEIMER'S
Many AD-related genes contain methylated CpG sites in their promoter regions, and a genome-wide decrease in DNA methylation has been reported in AD. In AD, both hypomethylation and hypermethylation of specific genes have been reported. The intracellular domain of APP (AICD) has emerged as a key epigenetic regulator of gene expression, controlling a diverse range of genes, including APP itself, the amyloid-degrading enzyme neprilysin, etc. Presenilin1 (PSEN1) is modulated by DNA methylation in neuroblastoma cells and Alzheimer’s mice in an experimental model of nutritionally altered one-carbon metabolism. Studies performed on human neuronal cell cultures revealed that deprivation of folate and other B vitamins results in epigenetic modification of PSEN1. Hyperphosphorylated tau is responsible for the formation of neurofibrillary tangles (NFTs). Changes in methylation status differ among transcription factor binding sites of tau promoter. Binding sites for GCF (granulocyte chemotactic factor), responsible for the repression of GC-rich promoters, were found to be hypomethylated, whereas binding sites for the transcriptional activator SP1 (specificity factor 1) were hypermethylated.
PHARMACOGENOMICS
Pharmacogenomics is the study of how genes affect a person's response to drugs. Pharmacogenomics accounts for 30%–90% variability in pharmacokinetics (the branch of pharmacology concerned with the movement of drugs within the body) and pharmacodynamics(the branch of pharmacology concerned with the effects of drugs and the mechanism of their action); however, pharmacogenetics alone does not predict all phenotypic variations in drug response. Individual differences in drug response are associated with genetic and epigenetic variability and disease determinants. The tissue-specific expression of genes involved in the pharmacogenetic processes is under epigenetic regulation; consequently, epigenetics plays a key role in drug efficacy and safety, and in drug resistance as well. Epigenetic changes affect cytochrome P450 enzyme expression, major transporter function, and nuclear receptor interactions.
