epigenetics epigenetics in biology, epigenetics is the study of stable changes in cell function (known as marks) that do not involve alterations in the dna sequence. the greek prefix epi- (ἐπι- "over, outside of, around") in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic basis for inheritance. epigenetics most often involves changes that affect the regulation of gene expression, and that persist through cellular division. such effects on cellular and physiological phenotypic traits may result from external or environmental factors, or be part of normal development. it can also lead to diseases such as cancer. epigenetic mechanisms the term also refers to the mechanism of changes: functionally relevant alterations to the genome that do not involve mutation of the nucleotide sequence. examples of mechanisms that produce such changes are dna methylation and histone modification, each of which alters how genes are expressed without altering the underlying dna sequence. gene expression can be controlled through the action of repressor proteins that attach to silencer regions of the dna. these epigenetic changes may last through cell divisions for the duration of the cell's life, and may also last for multiple generations, even though they do not involve changes in the underlying dna sequence of the organism; instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently. one example of an epigenetic change in eukaryotic biology is the process of cellular differentiation. during morphogenesis, totipotent stem cells become the various pluripotent cell lines of the embryo, which in turn become fully differentiated cells. in other words, as a single fertilized egg cell – the zygote – continues to divide, the resulting daughter cells change into all the different cell types in an organism, including neurons, muscle cells, epithelium, endothelium of blood vessels, etc., by activating some genes while inhibiting the expression of others. definitions the term epigenetics in its contemporary usage emerged in the 1990s, but for some years has been used with somewhat variable meanings. a definition of the concept of epigenetic trait as a "stably heritable phenotype resulting from changes in a chromosome without alterations in the dna sequence" was formulated at a cold spring harbor meeting in 2008, although alternate definitions that include non-heritable traits are still being used widely. the term epigenesis has a generic meaning of "extra growth" that has been used in english since the 17th century. waddington's canalisation, 1940s the hypothesis of epigenetic changes affecting the expression of chromosomes was put forth by the russian biologist nikolai koltsov. from the generic meaning, and the associated adjective epigenetic, british embryologist c. h. waddington coined the term epigenetics in 1942 as pertaining to epigenesis, in parallel to valentin haecker's 'phenogenetics' (phänogenetik). epigenesis in the context of the biology of that period referred to the differentiation of cells from their initial totipotent state during embryonic development. when waddington coined the term, the physical nature of genes and their role in heredity was not known. he used it instead as a conceptual model of how genetic components might interact with their surroundings to produce a phenotype; he used the phrase "epigenetic landscape" as a metaphor for biological development. waddington held that cell fates were established during development in a process he called canalisation much as a marble rolls down to the point of lowest local elevation. waddington suggested visualising increasing irreversibility of cell type differentiation as ridges rising between the valleys where the marbles (analogous to cells) are travelling. in recent times, waddington's notion of the epigenetic landscape has been rigorously formalized in the context of the systems dynamics state approach to the study of cell-fate. cell-fate determination is predicted to exhibit certain dynamics, such as attractor-convergence (the attractor can be an equilibrium point, limit cycle or strange attractor) or oscillatory. contemporary robin holliday defined in 1990 epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms." thus, in its broadest sense, epigenetic can be used to describe anything other than dna sequence that influences the development of an organism. more recent usage of the word in biology follows stricter definitions. as defined by arthur riggs and colleagues, it is "the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in dna sequence." the term has also been used, however, to describe processes which have not been demonstrated to be heritable, such as some forms of histone modification. consequently, there are attempts to redefine "epigenetics" in broader terms that would avoid the constraints of requiring heritability. for example, adrian bird defined epigenetics as "the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states." this definition would be inclusive of transient modifications associated with dna repair or cell-cycle phases as well as stable changes maintained across multiple cell generations, but exclude others such as templating of membrane architecture and prions unless they impinge on chromosome function. such redefinitions however are not universally accepted and are still subject to debate. the nih "roadmap epigenomics project", which ran from 2008 to 2017, uses the following definition: "for purposes of this program, epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable." in 2008, a consensus definition of the epigenetic trait, a "stably heritable phenotype resulting from changes in a chromosome without alterations in the dna sequence," was made at a cold spring harbor meeting. the similarity of the word to "genetics" has generated many parallel usages. the "epigenome" is a parallel to the word "genome," referring to the overall epigenetic state of a cell, and epigenomics refers to global analyses of epigenetic changes across the entire genome. the phrase "genetic code" has also been adapted – the "epigenetic code" has been used to describe the set of epigenetic features that create different phenotypes in different cells from the same underlying dna sequence. taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for in an epigenomic map, a diagrammatic representation of the gene expression, dna methylation and histone modification status of a particular genomic region. more typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the histone code or dna methylation patterns. developmental psychology in a sense somewhat unrelated to its use in any biological disciplines, the term "epigenetic" has also been used in developmental psychology to describe psychological development as the result of an ongoing, bi-directional interchange between heredity and the environment. interactive ideas of development have been discussed in various forms and under various names throughout the 19th and 20th centuries. an early version was proposed, among the founding statements in embryology, by karl ernst von baer and popularized by ernst haeckel. a radical epigenetic view, known as physiological epigenesis, was developed by paul wintrebert. another variation, probabilistic epigenesis, was presented by gilbert gottlieb in 2003. this view encompasses all of the possible developing factors on an organism and how they not only influence the organism and each other but how the organism also influences its own development. gottlieb gave an example of rhesus monkeys where infants that did not receive typical maternal care lacked serotonin, which in turn made them more aggressive as they got older. on another note, the long-standing notion "cells that fire together, wire together" derives from hebbian theory which asserts that synaptogenesis, a developmental process with great epigenetic precedence, depends on the activity of the respective synapses within a neural network. where experience alters the excitability of neurons, increased neural activity has been linked to increased demethylation . the developmental psychologist erik erikson wrote of an epigenetic principle in his 1968 book identity: youth and crisis, encompassing the notion that we develop through an unfolding of our personality in predetermined stages, and that our environment and surrounding culture influence how we progress through these stages. this biological unfolding in relation to our socio-cultural settings is done in stages of psychosocial development, where "progress through each stage is in part determined by our success, or lack of success, in all the previous stages." although empirical studies have yielded discrepant results, epigenetic modifications are thought to be a biological mechanism for transgenerational trauma. molecular basis epigenetic changes modify the activation of certain genes, but not the genetic code sequence of dna. the microstructure (not code) of dna itself or the associated chromatin proteins may be modified, causing activation or silencing. this mechanism enables differentiated cells in a multicellular organism to express only the genes that are necessary for their own activity. epigenetic changes are preserved when cells divide. most epigenetic changes only occur within the course of one individual organism's lifetime; however, these epigenetic changes can be transmitted to the organism's offspring through a process called transgenerational epigenetic inheritance. moreover, if gene inactivation occurs in a sperm or egg cell that results in fertilization, this epigenetic modification may also be transferred to the next generation. specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, x chromosome inactivation, position effect, dna methylation reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning. dna damage dna damage can also cause epigenetic changes. dna damage is very frequent, occurring on average about 60,000 times a day per cell of the human body (see dna damage (naturally occurring)). these damages are largely repaired, however, epigenetic changes can still remain at the site of dna repair. in particular, a double strand break in dna can initiate unprogrammed epigenetic gene silencing both by causing dna methylation as well as by promoting silencing types of histone modifications (chromatin remodeling - see next section). in addition, the enzyme parp1 (poly(adp)-ribose polymerase) and its product poly(adp)-ribose (par) accumulate at sites of dna damage as part of the repair process. this accumulation, in turn, directs recruitment and activation of the chromatin remodeling protein, alc1, that can cause nucleosome remodeling. nucleosome remodeling has been found to cause, for instance, epigenetic silencing of dna repair gene mlh1. dna damaging chemicals, such as benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene, cause considerable hypomethylation of dna, some through the activation of oxidative stress pathways. foods are known to alter the epigenetics of rats on different diets. some food components epigenetically increase the levels of dna repair enzymes such as mgmt and mlh1 and p53. other food components can reduce dna damage, such as soy isoflavones. in one study, markers for oxidative stress, such as modified nucleotides that can result from dna damage, were decreased by a 3-week diet supplemented with soy. a decrease in oxidative dna damage was also observed 2 h after consumption of anthocyanin-rich bilberry (vaccinium myrtillius l.) pomace extract. dna repair damage to dna is very common and is constantly being repaired. epigenetic alterations can accompany dna repair of oxidative damage or double-strand breaks. in human cells, oxidative dna damage occurs about 10,000 times a day and dna double-strand breaks occur about 10 to 50 times a cell cycle in somatic replicating cells (see dna damage (naturally occurring)). the selective advantage of dna repair is to allow the cell to survive in the face of dna damage. the selective advantage of epigenetic alterations that occur with dna repair is not clear. repair of oxidative dna damage can alter epigenetic markers in the steady state (with endogenous damages occurring and being repaired), there are about 2,400 oxidatively damaged guanines that form 8-oxo-2'-deoxyguanosine (8-ohdg) in the average mammalian cell dna. 8-ohdg constitutes about 5% of the oxidative damages commonly present in dna. the oxidized guanines do not occur randomly among all guanines in dna. there is a sequence preference for the guanine at a methylated cpg site (a cytosine followed by guanine along its 5' → 3' direction and where the cytosine is methylated (5-mcpg)). a 5-mcpg site has the lowest ionization potential for guanine oxidation. initiation of dna demethylation at a cpg site. in adult somatic cells dna methylation typically occurs in the context of cpg dinucleotides (cpg sites), forming