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In biology, epigenetics is the study of changes in gene expression that happen without changes to 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 (DNA sequence based) 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 traits may result from environmental factors, or be part of normal development.
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. Further, non-coding RNA sequences have been shown to play a key role in the regulation of gene expression. 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 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 of the embryo, which in turn become fully differentiated cells. In other words, as a single fertilized egg cell – the zygote – continues to mitosis, 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.
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.
When Waddington coined the term, the physical nature of 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 morphogenesis. 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 local optimum. (2025). 9781107440470, Cambridge University Press. ISBN 9781107440470 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 system 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.
More recent usage of the word in biology follows stricter definitions. As defined by Arthur Riggs and colleagues, it is "the study of mitosis and/or meiosis heritable changes in gene function that cannot be explained by changes in DNA sequence." (1996). 9780879694906, Cold Spring Harbor Laboratory Press. ISBN 9780879694906
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 gene 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.
Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression. One way that genes are regulated is through the remodeling of chromatin. Chromatin is the complex of DNA and the histone proteins with which it associates. If the way that DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:
There is frequently a reciprocal relationship between DNA methylation and histone lysine methylation. For instance, the methyl binding domain protein MBD1, attracted to and associating with methylated cytosine in a DNA CpG site, can also associate with H3K9 methyltransferase activity to methylate histone 3 at lysine 9. On the other hand, DNA maintenance methylation by DNMT1 appears to partly rely on recognition of histone methylation on the nucleosome present at the DNA site to carry out cytosine methylation on newly synthesized DNA. There is further crosstalk between DNA methylation carried out by DNMT3A and DNMT3B and histone methylation so that there is a correlation between the genome-wide distribution of DNA methylation and histone methylation.
Mechanisms of heritability of histone state are not well understood; however, much is known about the mechanism of heritability of DNA methylation state during cell division and differentiation. Heritability of methylation state depends on certain enzymes (such as DNMT1) that have a higher affinity for 5-methylcytosine than for cytosine. If this enzyme reaches a "hemimethylated" portion of DNA (where 5-methylcytosine is in only one of the two DNA strands) the enzyme will methylate the other half. However, it is now known that DNMT1 physically interacts with the protein UHRF1. UHRF1 has been recently recognized as essential for DNMT1-mediated maintenance of DNA methylation. UHRF1 is the protein that specifically recognizes hemi-methylated DNA, therefore bringing DNMT1 to its substrate to maintain DNA methylation.
Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation, ubiquitylation, phosphorylation, sumoylation, ribosylation and citrullination. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally related to transcriptional competence (see Figure).
One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, thus loosening the DNA from the histone. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA and allow transcription to occur. This is the "cis" model of the epigenetic function. In other words, changes to the histone tails have a direct effect on the DNA itself. (2025). 9780429174117 ISBN 9780429174117
Another model of epigenetic function is the "trans" model. In this model, changes to the histone tails act indirectly on the DNA. For example, lysine acetylation may create a binding site for chromatin-modifying enzymes (or transcription machinery as well). This chromatin remodeler can then cause changes to the state of the chromatin. Indeed, a bromodomain – a protein domain that specifically binds acetyl-lysine – is found in many enzymes that help activate transcription, including the SWI/SNF complex. It may be that acetylation acts in this and the previous way to aid in transcriptional activation.
The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin) (see bottom Figure). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein HP1 recruits HP1 to K9 methylated regions. One example that seems to refute this biophysical model for methylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation (see top Figure). Tri-methylation, in this case, would introduce a fixed positive charge on the tail.
It has been shown that the histone lysine methyltransferase (KMT) is responsible for this methylation activity in the pattern of histones H3 & H4. This enzyme utilizes a catalytically active site called the SET domain (Suppressor of variegation, Enhancer of Zeste, Trithorax). The SET domain is a 130-amino acid sequence involved in modulating gene activities. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone.
Differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently from acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code, although the idea that histone state can be read linearly as a digital information carrier has been largely debunked. One of the best-understood systems that orchestrate chromatin-based silencing is the SIR protein based silencing of the yeast hidden mating-type loci HML and HMR.
By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after DNA replication, and therefore is often referred to as the 'maintenance' methyltransferase. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation. To emphasize the difference of this molecular mechanism of inheritance from the canonical Watson-Crick base-pairing mechanism of transmission of genetic information, the term 'Epigenetic templating' was introduced. Furthermore, in addition to the maintenance and transmission of methylated DNA states, the same principle could work in the maintenance and transmission of histone modifications and even cytoplasmic (structural) heritable states.
Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of states of larger chromosomal regions are suggested to involve positive feedback where modified recruit enzymes that similarly modify nearby nucleosomes. A simplified stochastic model for this type of epigenetics is found here.
It has been suggested that chromatin-based transcriptional regulation could be mediated by the effect of small RNAs. Small interfering RNAs can modulate transcriptional gene expression via epigenetic modulation of targeted promoters. (2025). 9781904455257, Caister Academic Press. ISBN 9781904455257
It appears that about 60% of human protein coding genes are regulated by miRNAs. Many miRNAs are epigenetically regulated. About 50% of miRNA genes are associated with , that may be repressed by epigenetic methylation. Transcription from methylated CpG islands is strongly and heritably repressed. Other miRNAs are epigenetically regulated by either histone modifications or by combined DNA methylation and histone modification.
are considered by some to be epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast in 1965 and 1971, are the two best studied of this type of prion. Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop , an effect that results in suppression of nonsense mutations in other genes. The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to switch into a PSI+ state and express dormant genetic features normally terminated by stop codon mutations.
Prion-based epigenetics has also been observed in Saccharomyces cerevisiae.
Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X-inactivation, position effect, DNA methylation reprogramming, transvection, , the progress of carcinogenesis, many effects of , regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning. (2025). 9789811032318 ISBN 9789811032318
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.
Oxidized guanine has mispairing potential and is mutagenic. Oxoguanine glycosylase (OGG1) is the primary enzyme responsible for the excision of the oxidized guanine during DNA repair. OGG1 finds and binds to an 8-OHdG within a few seconds. However, OGG1 does not immediately excise 8-OHdG. In HeLa cells half maximum removal of 8-OHdG occurs in 30 minutes, and in irradiated mice, the 8-OHdGs induced in the mouse liver are removed with a half-life of 11 minutes.
When OGG1 is present at an oxidized guanine within a methylated CpG site it recruits TET enzymes to the 8-OHdG lesion (see Figure). This allows TET1 to demethylate an adjacent methylated cytosine. Demethylation of cytosine is an epigenetic alteration.
As an example, when human mammary epithelial cells were treated with H2O2 for six hours, 8-OHdG increased about 3.5-fold in DNA and this caused about 80% demethylation of the 5-methylcytosines in the genome. Demethylation of CpGs in a gene promoter by TET enzymes activity increases transcription of the gene into messenger RNA. In cells treated with H2O2, one particular gene was examined, BACE1. The methylation level of the BACE1 CpG island was reduced (an epigenetic alteration) and this allowed about 6.5 fold increase of expression of BACE1 messenger RNA.
While six-hour incubation with H2O2 causes considerable demethylation of 5-mCpG sites, shorter times of H2O2 incubation appear to promote other epigenetic alterations. Treatment of cells with H2O2 for 30 minutes causes the mismatch repair protein heterodimer MSH2-MSH6 to recruit DNA methyltransferase 1 (DNMT1) to sites of some kinds of oxidative DNA damage. This could cause increased methylation of cytosines (epigenetic alterations) at these locations.
Jiang et al. treated HEK 293 cells with agents causing oxidative DNA damage, (potassium bromate (KBrO3) or potassium chromate (K2CrO4)). Base excision repair (BER) of oxidative damage occurred with the DNA repair enzyme DNA polymerase localizing to oxidized guanines. Polymerase beta is the main human polymerase in short-patch BER of oxidative DNA damage. Jiang et al. also found that polymerase beta recruited the DNA methyltransferase protein DNMT3b to BER repair sites. They then evaluated the methylation pattern at the single nucleotide level in a small region of DNA including the promoter region and the early transcription region of the BRCA1 gene. Oxidative DNA damage from bromate modulated the DNA methylation pattern (caused epigenetic alterations) at CpG sites within the region of DNA studied. In untreated cells, CpGs located at −189, −134, −29, −19, +16, and +19 of the BRCA1 gene had methylated cytosines (where numbering is from the messenger RNA transcription start site, and negative numbers indicate nucleotides in the upstream promoter region). Bromate treatment-induced oxidation resulted in the loss of cytosine methylation at −189, −134, +16 and +19 while also leading to the formation of new methylation at the CpGs located at −80, −55, −21 and +8 after DNA repair was allowed.
In mice with a CRISPR-mediated homology-directed recombination insertion in their genome there were a large number of increased methylations of CpG sites within the double-strand break-associated insertion.
An event can set off a chain of reactions that result in altered methylations of a large set of genes in neurons, which give a representation of the event, a memory.
Areas of the brain important in the formation of memories include the hippocampus, medial prefrontal cortex (mPFC), anterior cingulate cortex and amygdala, as shown in the diagram of the human brain in this section.
When a strong memory is created, as in a rat subjected to contextual fear conditioning (CFC), one of the earliest events to occur is that more than 100 DNA double-strand breaks are formed by topoisomerase in neurons of the hippocampus and the medial prefrontal cortex (mPFC). These double-strand breaks are at specific locations that allow activation of transcription of immediate early genes (IEGs) that are important in memory formation, allowing their expression in messenger RNA, with peak mRNA transcription at seven to ten minutes after CFC.
Two important IEGs in memory formation are EGR1 and the alternative promoter variant of DNMT3A, DNMT3A2. EGR1 protein binds to DNA at its binding motifs, 5′-GCGTGGGCG-3′ or 5′-GCGGGGGCGG-3', and there are about 12,000 genome locations at which EGR1 protein can bind. EGR1 protein binds to DNA in gene promoter and enhancer regions. EGR1 recruits the demethylating enzyme TET enzymes to an association, and brings TET1 to about 600 locations on the genome where TET1 can then demethylate and activate the associated genes.
The DNA methyltransferases DNMT3A1, DNMT3A2 and DNMT3B can all methylate cytosines (see image this section) at in or near the promoters of genes. As shown by Manzo et al., these three DNA methyltransferases differ in their genomic binding locations and DNA methylation activity at different regulatory sites. Manzo et al. located 3,970 genome regions exclusively enriched for DNMT3A1, 3,838 regions for DNMT3A2 and 3,432 regions for DNMT3B. When DNMT3A2 is newly induced as an IEG (when neurons are activated), many new cytosine methylations occur, presumably in the target regions of DNMT3A2. Oliviera et al. found that the neuronal activity-inducible IEG levels of Dnmt3a2 in the hippocampus determined the ability to form long-term memories.
Rats form long-term associative memories after contextual fear conditioning (CFC). Duke et al. found that 24 hours after CFC in rats, in hippocampus neurons, 2,097 genes (9.17% of the genes in the rat genome) had altered methylation. When newly methylated cytosines are present in in the promoter regions of genes, the genes are often repressed, and when newly demethylated cytosines are present the genes may be activated. After CFC, there were 1,048 genes with reduced mRNA expression and 564 genes with upregulated mRNA expression. Similarly, when mice undergo CFC, one hour later in the hippocampus region of the mouse brain there are 675 demethylated genes and 613 hypermethylated genes. However, memories do not remain in the hippocampus, but after four or five weeks the memories are stored in the anterior cingulate cortex. In the studies on mice after CFC, Halder et al. showed that four weeks after CFC there were at least 1,000 differentially methylated genes and more than 1,000 differentially expressed genes in the anterior cingulate cortex, while at the same time the altered methylations in the hippocampus were reversed.
The epigenetic alteration of methylation after a new memory is established creates a different pool of nuclear mRNAs. As reviewed by Bernstein, the epigenetically determined new mix of nuclear messenger RNA are often packaged into neuronal granules, or messenger RNP, consisting of mRNA, ribosome, translation initiation factors and RNA-binding proteins that regulate mRNA function. These neuronal granules are transported from the neuron nucleus and are directed, according to 3′ untranslated regions of the mRNA in the granules (their "zip codes"), to neuronal . Roughly 2,500 mRNAs may be localized to the dendrites of hippocampal pyramidal neurons and perhaps 450 transcripts are in excitatory presynaptic nerve terminals (dendritic spines). The altered assortments of transcripts (dependent on epigenetic alterations in the neuron nucleus) have different sensitivities in response to signals, which is the basis of altered synaptic plasticity. Altered synaptic plasticity is often considered the neurochemical foundation of learning and memory.
Early events, including during embryonic development, can influence development, cognition, and health outcomes through epigenetic mechanisms.
Epigenetic mechanisms have been proposed as "a potential molecular mechanism for effects of endogenous on the organization of developing brain circuits". (2025). 9780128234662 ISBN 9780128234662
Nutrients could interact with the epigenome to "protect or boost cognitive processes across the lifespan".
A review suggests neurobiological effects of physical exercise via epigenetics seem "central to building an 'epigenetic memory' to influence long-term brain function and behavior" and may even be heritable.
With the axo-ciliary synapse, there is communication between Serotonin and antenna-like primary cilia of CA1 Pyramidal cell that alters the neuron's epigenetic state in the Cell nucleus via the signalling distinct from that at the plasma membrane (and longer-term).
Epigenetics also play a major role in the brain evolution in and to humans.
Somatic epigenetic inheritance, particularly through DNA and histone covalent modifications and nucleosome repositioning, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate into many different types, which perform different functions, and respond differently to the environment and intercellular signaling. Thus, as individuals develop, activate or silence genes in an epigenetically heritable fashion, giving cells a memory. In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In , some stem cells continue producing newly differentiated cells throughout life, such as in neurogenesis, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Epigenetic modifications regulate the transition from neural stem cells to glial progenitor cells (for example, differentiation into oligodendrocytes is regulated by the deacetylation and methylation of histones).Chapter: "Nervous System Development" in "Epigenetics," by Benedikt Hallgrimsson and Brian Hall Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilize many of the same epigenetic mechanisms as animals, such as chromatin remodeling, it has been hypothesized that some kinds of plant cells do not use or require "cellular memories", resetting their gene expression patterns using positional information from the environment and surrounding cells to determine their fate.
Epigenetic changes can occur in response to environmental exposure – for example, maternal dietary supplementation with genistein (250 mg/kg) have epigenetic changes affecting expression of the agouti gene, which affects their fur color, weight, and propensity to develop cancer. Ongoing research is focused on exploring the impact of other known , such as diabetic embryopathy, on methylation signatures.
Controversial results from one study suggested that traumatic experiences might produce an epigenetic signal that is capable of being passed to future generations. Mice were trained, using foot shocks, to fear a cherry blossom odor. The investigators reported that the mouse offspring had an increased aversion to this specific odor. They suggested epigenetic changes that increase gene expression, rather than in DNA itself, in a gene, M71, that governs the functioning of an odor receptor in the nose that responds specifically to this cherry blossom smell. There were physical changes that correlated with olfactory (smell) function in the brains of the trained mice and their descendants. Several criticisms were reported, including the study's low statistical power as evidence of some irregularity such as bias in reporting results. Due to limits of sample size, there is a probability that an effect will not be demonstrated to within statistical significance even if it exists. The criticism suggested that the probability that all the experiments reported would show positive results if an identical protocol was followed, assuming the claimed effects exist, is merely 0.4%. The authors also did not indicate which mice were siblings, and treated all of the mice as statistically independent. (see comment by Gonzalo Otazu) The original researchers pointed out negative results in the paper's appendix that the criticism omitted in its calculations, and undertook to track which mice were siblings in the future.
A sequestered germ line or Weismann barrier is specific to animals, and epigenetic inheritance is more common in plants and microbes. Eva Jablonka, Marion J. Lamb and Étienne Danchin have argued that these effects may require enhancements to the standard conceptual framework of the modern synthesis and have called for an extended evolutionary synthesis. (2025). 9780262101073, MIT Press. ISBN 9780262101073See also Denis Noble: The Music of Life, esp pp. 93–98 and p. 48, where he cites Jablonka & Lamb and Massimo Pigliucci's review of Jablonka and Lamb in Nature 435, 565–566 (2 June 2005) Other evolutionary biologists, such as John Maynard Smith, have incorporated epigenetic inheritance into population-genetics models or are openly skeptical of the extended evolutionary synthesis (Michael Lynch). Thomas Dickins and Qazi Rahman state that epigenetic mechanisms such as DNA methylation and histone modification are genetically inherited under the control of natural selection and therefore fit under the earlier "modern synthesis".
Two important ways in which epigenetic inheritance can differ from traditional genetic inheritance, with important consequences for evolution, are:
In plants, heritable DNA methylation mutations are 100,000 times more likely to occur compared to DNA mutations. An epigenetically inherited element such as the PSI+ system can act as a "stop-gap", good enough for short-term adaptation that allows the lineage to survive for long enough for mutation and/or recombination to genetically assimilate the adaptive phenotypic change. The existence of this possibility increases the evolvability of a species.
More than 100 cases of transgenerational epigenetic inheritance phenomena have been reported in a wide range of organisms, including prokaryotes, plants, and animals. For instance, mourning-cloak butterflies will change color through hormone changes in response to experimentation of varying temperatures.Davies, Hazel (2008). Do Butterflies Bite?: Fascinating Answers to Questions about Butterflies and Moths (Animals Q&A). Rutgers University Press.
The filamentous fungus Neurospora crassa is a prominent model system for understanding the control and function of cytosine methylation. In this organism, DNA methylation is associated with relics of a genome-defense system called RIP (repeat-induced point mutation) and silences gene expression by inhibiting transcription elongation.
The yeast prion PSI is generated by a conformational change of a translation termination factor, which is then inherited by daughter cells. This can provide a survival advantage under adverse conditions, exemplifying epigenetic regulation which enables unicellular organisms to respond rapidly to environmental stress. Prions can be viewed as epigenetic agents capable of inducing a phenotypic change without modification of the genome. (2025). 9781904455233, Caister Academic Press. ISBN 9781904455233
Direct detection of epigenetic marks in microorganisms is possible with single molecule real time sequencing, in which polymerase sensitivity allows for measuring methylation and other modifications as a DNA molecule is being sequenced. Several projects have demonstrated the ability to collect genome-wide epigenetic data in bacteria.
Dizygotic (fraternal) and monozygotic (identical) twins show evidence of epigenetic influence in humans. DNA sequence differences that would be abundant in a singleton-based study do not interfere with the analysis. Environmental differences can produce long-term epigenetic effects, and different developmental monozygotic twin subtypes may be different with respect to their susceptibility to be discordant from an epigenetic point of view.
A high-throughput study, which denotes technology that looks at extensive genetic markers, focused on epigenetic differences between monozygotic twins to compare global and locus-specific changes in DNA methylation and histone modifications in a sample of 40 monozygotic twin pairs. In this case, only healthy twin pairs were studied, but a wide range of ages was represented, between 3 and 74 years. One of the major conclusions from this study was that there is an age-dependent accumulation of epigenetic differences between the two siblings of twin pairs. This accumulation suggests the existence of epigenetic "drift". Epigenetic drift is the term given to epigenetic modifications as they occur as a direct function with age. While age is a known risk factor for many diseases, age-related methylation has been found to occur differentially at specific sites along the genome. Over time, this can result in measurable differences between biological and chronological age. Epigenetic changes have been found to be reflective of lifestyle and may act as functional of disease before clinical reference range is reached.
A more recent study, where 114 monozygotic twins and 80 dizygotic twins were analyzed for the DNA methylation status of around 6000 unique genomic regions, concluded that epigenetic similarity at the time of blastocyst splitting may also contribute to phenotypic similarities in monozygotic co-twins. This supports the notion that microenvironment at early stages of embryonic development can be quite important for the establishment of epigenetic marks. Congenital genetic disease is well understood and it is clear that epigenetics can play a role, for example, in the case of Angelman syndrome and Prader–Willi syndrome. These are normal genetic diseases caused by gene deletions or inactivation of the genes but are unusually common because individuals are essentially hemizygous because of genomic imprinting, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.
In the Överkalix study, paternal (but not maternal) grandsonsA person's paternal grandson is the son of a son of that person; a maternal grandson is the son of a daughter. of Swedish men who were exposed during preadolescence to famine in the 19th century were less likely to die of cardiovascular disease. If food was plentiful, then diabetes mortality in the grandchildren increased, suggesting that this was a transgenerational epigenetic inheritance. Robert Winston refers to this study in a The opposite effect was observed for females – the paternal (but not maternal) granddaughters of women who experienced famine while in the womb (and therefore while their eggs were being formed) lived shorter lives on average.
Parental nutrition, in utero exposure to stress or endocrine disrupting chemicals, male-induced maternal effects such as the attraction of differential mate quality, and maternal as well as paternal age, and offspring gender could all possibly influence whether a germline epimutation is ultimately expressed in offspring and the degree to which intergenerational inheritance remains stable throughout posterity. (2025). 9780128093245 ISBN 9780128093245 However, whether and to what extent epigenetic effects can be transmitted across generations remains unclear, particularly in humans.
Fluoroquinolone antibiotics induce epigenetic changes in mammalian cells through iron chelation. This leads to epigenetic effects through inhibition of α-ketoglutarate-dependent dioxygenases that require iron as a co-factor.
Various pharmacological agents are applied for the production of induced pluripotent stem cells (iPSC) or maintain the embryonic stem cell (ESC) phenotypic via epigenetic approach. Adult stem cells like bone marrow stem cells have also shown a potential to differentiate into cardiac competent cells when treated with G9a histone methyltransferase inhibitor BIX01294.
Cell plasticity, which is the adaptation of cells to stimuli without changes in their genetic code, requires epigenetic changes. These have been observed in cell plasticity in cancer cells during epithelial-to-mesenchymal transition and also in immune cells, such as macrophages. Interestingly, metabolic changes underlie these adaptations, since various metabolites play crucial roles in the chemistry of epigenetic marks. This includes for instance alpha-ketoglutarate, which is required for histone demethylation, and acetyl-Coenzyme A, which is required for histone acetylation.
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