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In biology, epigenetics is the study of heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.
A maternal effect is a situation where the phenotype of an organism is determined not only by the environment it experiences and its genotype, but also by the environment and genotype of its mother. In genetics, maternal effects occur when an organism shows the phenotype expected from the genotype of the mother, irrespective of its own genotype, often due to the mother supplying messenger RNA or proteins to the egg. Maternal effects can also be caused by the maternal environment independent of genotype, sometimes controlling the size, sex, or behaviour of the offspring. These adaptive maternal effects lead to phenotypes of offspring that increase their fitness. Further, it introduces the concept of phenotypic plasticity, an important evolutionary concept. It has been proposed that maternal effects are important for the evolution of adaptive responses to environmental heterogeneity.
In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as RNA and proteins, in response to an external stimulus. The complementary process that involves increase in quantities of cellular components is called upregulation.
Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.
Computational epigenetics uses statistical methods and mathematical modelling in epigenetic research. Due to the recent explosion of epigenome datasets, computational methods play an increasing role in all areas of epigenetic research.
Manel Esteller graduated in medicine from the University of Barcelona in 1992, where he also obtained his doctorate, specializing in the molecular genetics of endometrial carcinoma, in 1996. He was an invited researcher at the School of Biological and Medical Sciences at the University of St Andrews, Scotland, during which time his research interests focused on the molecular genetics of inherited breast cancer.
Nutriepigenomics is the study of food nutrients and their effects on human health through epigenetic modifications. There is now considerable evidence that nutritional imbalances during gestation and lactation are linked to non-communicable diseases, such as obesity, cardiovascular disease, diabetes, hypertension, and cancer. If metabolic disturbances occur during critical time windows of development, the resulting epigenetic alterations can lead to permanent changes in tissue and organ structure or function and predispose individuals to disease.
Transgenerational epigenetic inheritance is the transmission of epigenetic markers and modifications from one generation to multiple subsequent generations without altering the primary structure of DNA. Thus, the regulation of genes via epigenetic mechanisms can be heritable; the amount of transcripts and proteins produced can be altered by inherited epigenetic changes. In order for epigenetic marks to be heritable, however, they must occur in the gametes in animals, but since plants lack a definitive germline and can propagate, epigenetic marks in any tissue can be heritable.
Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.
In recent years it has become apparent that the environment and underlying mechanisms affect gene expression and the genome outside of the central dogma of biology. It has been found that many epigenetic mechanisms are involved in the regulation and expression of genes such as DNA methylation and chromatin remodeling. These epigenetic mechanisms are believed to be a contributing factor to pathological diseases such as type 2 diabetes. An understanding of the epigenome of diabetes patients may help to elucidate otherwise hidden causes of this disease.
The epigenetics of schizophrenia is the study of how inherited epigenetic changes are regulated and modified by the environment and external factors and how these changes influence the onset and development of, and vulnerability to, schizophrenia. Epigenetics concerns the heritability of those changes, too. Schizophrenia is a debilitating and often misunderstood disorder that affects up to 1% of the world's population. Although schizophrenia is a heavily studied disorder, it has remained largely impervious to scientific understanding; epigenetics offers a new avenue for research, understanding, and treatment.
An epigenetic clock is a biochemical test that can be used to measure age. The test is based on DNA methylation levels, measuring the accumulation of methyl groups to one's DNA molecules.
Epigenetic therapy refers to the use of drugs or other interventions to modify gene expression patterns, potentially treating diseases by targeting epigenetic mechanisms such as DNA methylation and histone modifications.
An epigenome-wide association study (EWAS) is an examination of a genome-wide set of quantifiable epigenetic marks, such as DNA methylation, in different individuals to derive associations between epigenetic variation and a particular identifiable phenotype/trait. When patterns change such as DNA methylation at specific loci, discriminating the phenotypically affected cases from control individuals, this is considered an indication that epigenetic perturbation has taken place that is associated, causally or consequentially, with the phenotype.
Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.
Folami Ideraabdullah is an American geneticist and assistant professor in the Department of Genetics and the Department of Nutrition at the Gillings School of Global Public Health at the University of North Carolina at Chapel Hill. Ideraabdullah explores how maternal nutrition and environmental toxin exposure affect development through exploring epigenetic changes to DNA. She has found that maternal Vitamin D deficiencies can cause genome-wide changes in methylation patterns that persist for several generations and impact offspring health. Her international collaboration with the University of Witwatersrand represents the first time that metal levels in the placenta have been investigated in relation to birth outcomes in South Africa.
Andrea Baccarelli is an Italian American epigeneticist and clinical endocrinologist, best known for his academic contributions in the field of epigenetics, mitochondriomics, and computational epigenomics, with a research focus on investigating the impact of environmental exposures on human health. He currently serves as Dean of the Faculty at the Harvard T. H. Chan School of Public Health.
Linda Sharples is a British statistician who is Professor of Medical Statistics at the London School of Hygiene & Tropical Medicine. Her research considers statistical analysis of medical interventions. She has provided expert advice to clinical trials on cardiovascular disease, diabetes and cancer.
Nutritional epigenetics is a science that studies the effects of nutrition on gene expression and chromatin accessibility. It is a subcategory of nutritional genomics that focuses on the effects of bioactive food components on epigenetic events.
Epiphenotyping involves studying the relationship between DNA methylation patterns and phenotypic traits in individuals and populations to be able to predict a phenotype from a DNA methylation profile. In the following sections, the background of epiphenotyping, an overview of a general methodology, its applications, advantages, and limitations are covered.
References
- ↑ "Caroline Relton | HCEO". hceconomics.uchicago.edu. Retrieved 2024-03-30.
- ↑ "The identification and characterisation of genes associated with insulin resistance | WorldCat.org". search.worldcat.org. Retrieved 2024-03-29.
- ↑ "Richard Doll Seminar - Embracing epigenetics in epidemiological studies: uses in prediction and understanding disease mechanisms". www.ndph.ox.ac.uk. Retrieved 2024-03-30.
- 1 2 "Caroline Relton". Bristol Biomedical Research Centre. Retrieved 2024-03-29.
- ↑ Bristol, University of. "Caroline Relton". www.bristol.ac.uk. Retrieved 2024-03-30.
- 1 2 Bristol, University of. "2012: Children of the 90s | News and features | University of Bristol". www.bristol.ac.uk. Retrieved 2024-03-30.
- ↑ Pearce, Mark S; Mann, Kay D; Relton, Caroline L; Francis, Roger M; Steele, James G; Craft, Alan W; Parker, Louise (May 2012). "How the Newcastle Thousand Families birth cohort study has contributed to the understanding of the impact of birth weight and early life socioeconomic position on disease in later life". Maturitas. 72 (1): 23–28. doi:10.1016/j.maturitas.2012.02.005. ISSN 0378-5122. PMID 22391388.
- ↑ "Region's scientists help in cancer breakthrough". The Northern Echo. 2010-06-16. Retrieved 2024-03-30.
- ↑ "Executive Office | Governance | LSHTM". www.lshtm.ac.uk. Retrieved 2024-03-30.
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