title: Estrogen

text: Local application of estrogen in the rat hippocampus has been shown to inhibit the re-uptake of serotonin. Contrarily, local application of estrogen has been shown to block the ability of fluvoxamine to slow serotonin clearance, suggesting that the same pathways which are involved in SSRI efficacy may also be affected by components of local estrogen signaling pathways.


title: Estrogen

text: Studies have also found that fathers had lower levels of cortisol and testosterone but higher levels of estrogen (estradiol) than did non-fathers.


title: Estrogen

text: Estrogen may play a role in suppressing binge eating. Hormone replacement therapy using estrogen may be a possible treatment for binge eating behaviors in females. Estrogen replacement has been shown to suppress binge eating behaviors in female mice. The mechanism by which estrogen replacement inhibits binge-like eating involves the replacement of serotonin (5-HT) neurons. Women exhibiting binge eating behaviors are found to have increased brain uptake of neuron 5-HT, and therefore less of the neurotransmitter serotonin in the cerebrospinal fluid. Estrogen works to activate 5-HT neurons, leading to suppression of binge like eating behaviors.


title: Estrogen

text: It is also suggested that there is an interaction between hormone levels and eating at different points in the female menstrual cycle. Research has predicted increased emotional eating during hormonal flux, which is characterized by high progesterone and estradiol levels that occur during the mid-luteal phase. It is hypothesized that these changes occur due to brain changes across the menstrual cycle that are likely a genomic effect of hormones. These effects produce menstrual cycle changes, which result in hormone release leading to behavioral changes, notably binge and emotional eating. These occur especially prominently among women who are genetically vulnerable to binge eating phenotypes.


title: Estrogen

text: Binge eating is associated with decreased estradiol and increased progesterone. Klump et al. Progesterone may moderate the effects of low estradiol (such as during dysregulated eating behavior), but that this may only be true in women who have had clinically diagnosed binge episodes (BEs). Dysregulated eating is more strongly associated with such ovarian hormones in women with BEs than in women without BEs.


title: Estrogen

text: The implantation of 17β-estradiol pellets in ovariectomized mice significantly reduced binge eating behaviors and injections of GLP-1 in ovariectomized mice decreased binge-eating behaviors.


title: Estrogen

text: In rodents, estrogens (which are locally aromatized from androgens in the brain) play an important role in psychosexual differentiation, for example, by masculinizing territorial behavior; the same is not true in humans. In humans, the masculinizing effects of prenatal androgens on behavior (and other tissues, with the possible exception of effects on bone) appear to act exclusively through the androgen receptor. Consequently, the utility of rodent models for studying human psychosexual differentiation has been questioned.


title: Estrogen

text: Estrogens are responsible for both the pubertal growth spurt, which causes an acceleration in linear growth, and epiphyseal closure, which limits height and limb length, in both females and males. In addition, estrogens are responsible for bone maturation and maintenance of bone mineral density throughout life. Due to hypoestrogenism, the risk of osteoporosis increases during menopause.


title: Estrogen

text: Women are less impacted by heart disease due to vasculo-protective action of estrogen which helps in preventing atherosclerosis. It also helps in maintaining the delicate balance between fighting infections and protecting arteries from damage thus lowering the risk of cardiovascular disease. During pregnancy, high levels of estrogens increase coagulation and the risk of venous thromboembolism. Estrogen has been shown to upregulate the peptide hormone adropin.


title: Estrogen

text: Estrogen has anti-inflammatory properties and helps in mobilization of polymorphonuclear white blood cells or neutrophils.


title: Estrogen

text: Researchers have implicated estrogens in various estrogen-dependent conditions, such as ER-positive breast cancer, as well as a number of genetic conditions involving estrogen signaling or metabolism, such as estrogen insensitivity syndrome, aromatase deficiency, and aromatase excess syndrome.


title: Estrogen

text: Estrogens, in females, are produced primarily by the ovaries, and during pregnancy, the placenta. Follicle-stimulating hormone (FSH) stimulates the ovarian production of estrogens by the granulosa cells of the ovarian follicles and corpora lutea. Some estrogens are also produced in smaller amounts by other tissues such as the liver, pancreas, bone, adrenal glands, skin, brain, adipose tissue, and the breasts. These secondary sources of estrogens are especially important in postmenopausal women.


title: Estrogen

text: The pathway of estrogen biosynthesis in extragonadal tissues is different. These tissues are not able to synthesize C19 steroids, and therefore depend on C19 supplies from other tissues and the level of aromatase.


title: Estrogen

text: In females, synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of weak androgenic activity which serves predominantly as a precursor for more potent androgens such as testosterone as well as estrogen. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted either immediately into estrone, or into testosterone and then estradiol in an additional step. The conversion of androstenedione to testosterone is catalyzed by 17β-hydroxysteroid dehydrogenase (17β-HSD), whereas the conversion of androstenedione and testosterone into estrone and estradiol, respectively is catalyzed by aromatase, enzymes which are both expressed in granulosa cells. In contrast, granulosa cells lack 17α-hydroxylase and 17,20-lyase, whereas theca cells express these enzymes and 17β-HSD but lack aromatase. Hence, both granulosa and theca cells are essential for the production of estrogen in the ovaries.


title: Estrogen

text: Estrogen levels vary through the menstrual cycle, with levels highest near the end of the follicular phase just before ovulation.


title: Estrogen

text: Note that in males, estrogen is also produced by the Sertoli cells when FSH binds to their FSH receptors.


title: Estrogen

text: Estrogens are plasma protein bound to albumin and/or sex hormone-binding globulin in the circulation.


title: Estrogen

text: Estrogens are metabolized via hydroxylation by cytochrome P450 enzymes such as CYP1A1 and CYP3A4 and via conjugation by estrogen sulfotransferases (sulfation) and UDP-glucuronyltransferases (glucuronidation). In addition, estradiol is dehydrogenated by 17β-hydroxysteroid dehydrogenase into the much less potent estrogen estrone. These reactions occur primarily in the liver, but also in other tissues.


title: Estrogen

text: Estrogens are used as medications, mainly in hormonal contraception, hormone replacement therapy, and to treat gender dysphoria in transgender women and other transfeminine individuals as part of feminizing hormone therapy.


title: Estrogen

text: In 1929, Adolf Butenandt and Edward Adelbert Doisy independently isolated and purified estrone, the first estrogen to be discovered. Then, estriol and estradiol were discovered in 1930 and 1933, respectively. Shortly following their discovery, estrogens, both natural and synthetic, were introduced for medical use. Examples include estriol glucuronide (Emmenin, Progynon), estradiol benzoate, conjugated estrogens (Premarin), diethylstilbestrol, and ethinylestradiol.


title: Estrogen

text: The word estrogen derives from Ancient Greek. It is derived from "oestros" (a periodic state of sexual activity in female mammals), and genos (generating). It was first published in the early 1920s and referenced as "oestrin". With the years, American English adapted the spelling of estrogen to fit with its phonetic pronunciation. Nevertheless, both estrogen and oestrogen are used nowadays, yet some still wish to maintain its original spelling as it reflects the origin of the word.


title: Estrogen

text: The name "estrogen" is derived from the Greek (), literally meaning "verve" or "inspiration" but figuratively sexual passion or desire, and the suffix "-gen", meaning "producer of".


title: Estrogen

text: A range of synthetic and natural substances that possess estrogenic activity have been identified in the environment and are referred to xenoestrogens.


title: Estrogen

text: Estrogens are among the wide range of endocrine-disrupting compounds (EDCs) because they have high estrogenic potency. When an EDC makes its way into the environment, it may cause male reproductive dysfunction to wildlife and humans. The estrogen excreted from farm animals makes its way into fresh water systems. During the germination period of reproduction the fish are exposed to low levels of estrogen which may cause reproductive dysfunction to male fish.


title: Estrogen

text: Some hair shampoos on the market include estrogens and placental extracts; others contain phytoestrogens. In 1998, there were case reports of four prepubescent African-American girls developing breasts after exposure to these shampoos. In 1993, the FDA determined that not all over-the-counter topically applied hormone-containing drug products for human use are generally recognized as safe and effective and are misbranded. An accompanying proposed rule deals with cosmetics, concluding that any use of natural estrogens in a cosmetic product makes the product an unapproved new drug and that any cosmetic using the term "hormone" in the text of its labeling or in its ingredient statement makes an implied drug claim, subjecting such a product to regulatory action.


title: Estrogen

text: In addition to being considered misbranded drugs, products claiming to contain placental extract may also be deemed to be misbranded cosmetics if the extract has been prepared from placentas from which the hormones and other biologically active substances have been removed and the extracted substance consists principally of protein. The FDA recommends that this substance be identified by a name other than "placental extract" and describing its composition more accurately because consumers associate the name "placental extract" with a therapeutic use of some biological activity.


title: Epigenetics

text: In biology, epigenetics is the study of stable phenotypic changes (known as "marks") that do not involve alterations in the DNA sequence. The Greek prefix "epi-" ( "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, but the term can also be used to describe any heritable phenotypic change. Such effects on cellular and physiological phenotypic traits may result from external or environmental factors, or be part of normal development.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: The term "epigenesis" has a generic meaning of "extra growth" that has been used in English since the 17th century.


title: Epigenetics

text: 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' (). "Epigenesis" in the context of the biology of that period referred to the differentiation of cells from their initial totipotent state during embryonic development.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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."


title: Epigenetics

text: 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", ongoing as of 2016, 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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 .


title: Epigenetics

text: 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."


title: Epigenetics

text: Although empirical studies have yielded discrepant results, epigenetic modifications are thought to be a biological mechanism for transgenerational trauma.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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 mamalian 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: When OGG1 is present at an oxidized guanine within a methylated CpG site it recruits TET1 to the 8-OHdG lesion (see Figure). This allows TET1 to demethylate an adjacent methylated cytosine. Demethylation of cytosine is an epigenetic alteration.


title: Epigenetics

text: As an example, when human mammary epithelial cells were treated with HO 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 enzyme activity increases transcription of the gene into messenger RNA. In cells treated with HO, 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.


title: Epigenetics

text: While six-hour incubation with HO causes considerable demethylation of 5-mCpG sites, shorter times of HO incubation appear to promote other epigenetic alterations. Treatment of cells with HO 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.


title: Epigenetics

text: 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 polymerase beta 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.


title: Epigenetics

text: At least four articles report the recruitment of DNA methyltransferase 1 (DNMT1) to sites of DNA double-strand breaks. During homologous recombinational repair (HR) of the double-strand break, the involvement of DNMT1 causes the two repaired strands of DNA to have different levels of methylated cytosines. One strand becomes frequently methylated at about 21 CpG sites downstream of the repaired double-strand break. The other DNA strand loses methylation at about six CpG sites that were previously methylated downstream of the double-strand break, as well as losing methylation at about five CpG sites that were previously methylated upstream of the double-strand break. When the chromosome is replicated, this gives rise to one daughter chromosome that is heavily methylated downstream of the previous break site and one that is unmethylated in the region both upstream and downstream of the previous break site. With respect to the gene that was broken by the double-strand break, half of the progeny cells express that gene at a high level and in the other half of the progeny cells expression of that gene is repressed. When clones of these cells were maintained for three years, the new methylation patterns were maintained over that time period.


title: Epigenetics

text: 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.


title: Epigenetics

text: Non-homologous end joining (NHEJ) repair of a double-strand break can cause a small number of demethylations of pre-existing cytosine DNA methylations downstream of the repaired double-strand break. Further work by Allen et al. showed that NHEJ of a DNA double-strand break in a cell could give rise to some progeny cells having repressed expression of the gene harboring the initial double-strand break and some progeny having high expression of that gene due to epigenetic alterations associated with NHEJ repair. The frequency of epigenetic alterations causing repression of a gene after an NHEJ repair of a DNA double-strand break in that gene may be about 0.9%.


title: Epigenetics

text: Epigenetic research uses a wide range of molecular biological techniques to further understanding of epigenetic phenomena. These techniques include chromatin immunoprecipitation (together with its large-scale variants ChIP-on-chip and ChIP-Seq), fluorescent in situ hybridization, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification (DamID) and bisulfite sequencing. Furthermore, the use of bioinformatics methods has a role in computational epigenetics.


title: Epigenetics

text: Chromatin Immunoprecipitation (ChIP) has helped bridge the gap between DNA and epigenetic interactions. With the use of ChIP, researchers are able to make findings in regards to gene regulation, transcription mechanisms, and chromatin structure.


title: Epigenetics

text: Fluorescent "in situ" hybridization (FISH) is very important to understand epigenetic mechanisms. FISH can be used to find the location of genes on chromosomes, as well as finding noncoding RNAs. FISH is predominantly used for detecting chromosomal abnormalities in humans.


title: Epigenetics

text: Methylation sensitive restriction enzymes paired with PCR is a way to evaluate methylation in DNA - specifically the CpG sites. If DNA is methylated, the restriction enzymes will not cleave the strand. Contrarily, if the DNA is not methylated, the enzymes will cleave the strand and it will be amplified by PCR.


title: Epigenetics

text: Bisulfite sequencing is another way to evaluate DNA methylation. Cytosine will be changed to uracil from being treated with sodium bisulfite, whereas methylated cytosines will not be affected.


title: Epigenetics

text: Epigenetic mechanisms are sensitive to environmental effects, and key participants in shaping an adult phenotype. Several types of epigenetic inheritance systems may play a role in what has become known as cell memory, note however that not all of these are universally accepted to be examples of epigenetics.


title: Epigenetics

text: Covalent modification of either DNA (e.g. cytosine methylation and hydroxymethylation) or of histone proteins (e.g. lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation) play central roles in many types of epigenetic inheritance. Therefore, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodeling is not always inherited, and not all epigenetic inheritance involves chromatin remodeling. In 2019, a further lysine modification appeared in the scientific literature linking epigenetics modification to cell metabolism, i.e. Lactylation


title: Epigenetics

text: 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:


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally related to transcriptional competence (see Figure).


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: DNA methylation frequently occurs in repeated sequences, and helps to suppress the expression and mobility of 'transposable elements': Because 5-methylcytosine can be spontaneously deaminated (replacing nitrogen by oxygen) to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B, the loss of any of which is lethal in mice. DNMT1 is the most abundant methyltransferase in somatic cells, localizes to replication foci, has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).


title: Epigenetics

text: 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.


title: Epigenetics

text: Histones H3 and H4 can also be manipulated through demethylation using histone lysine demethylase (KDM). This recently identified enzyme has a catalytically active site called the Jumonji domain (JmjC). The demethylation occurs when JmjC utilizes multiple cofactors to hydroxylate the methyl group, thereby removing it. JmjC is capable of demethylating mono-, di-, and tri-methylated substrates.


title: Epigenetics

text: 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 nucleosomes recruit enzymes that similarly modify nearby nucleosomes. A simplified stochastic model for this type of epigenetics is found here.


title: Epigenetics

text: 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.


title: Epigenetics

text: Sometimes a gene, after being turned on, transcribes a product that (directly or indirectly) maintains the activity of that gene. For example, Hnf4 and MyoD enhance the transcription of many liver-specific and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. RNA signalling includes differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. Other epigenetic changes are mediated by the production of different splice forms of RNA, or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effect phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.


title: Epigenetics

text: MicroRNAs (miRNAs) are members of non-coding RNAs that range in size from 17 to 25 nucleotides. miRNAs regulate a large variety of biological functions in plants and animals. So far, in 2013, about 2000 miRNAs have been discovered in humans and these can be found online in a miRNA database. Each miRNA expressed in a cell may target about 100 to 200 messenger RNAs(mRNAs) that it downregulates. Most of the downregulation of mRNAs occurs by causing the decay of the targeted mRNA, while some downregulation occurs at the level of translation into protein.


title: Epigenetics

text: 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 CpG islands, 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.


title: Epigenetics

text: In 2011, it was demonstrated that the methylation of mRNA plays a critical role in human energy homeostasis. The obesity-associated FTO gene is shown to be able to demethylate N6-methyladenosine in RNA.


title: Epigenetics

text: sRNAs are small (50–250 nucleotides), highly structured, non-coding RNA fragments found in bacteria. They control gene expression including virulence genes in pathogens and are viewed as new targets in the fight against drug-resistant bacteria. They play an important role in many biological processes, binding to mRNA and protein targets in prokaryotes. Their phylogenetic analyses, for example through sRNA–mRNA target interactions or protein binding properties, are used to build comprehensive databases. sRNA-gene maps based on their targets in microbial genomes are also constructed.


title: Epigenetics

text: Prions are infectious forms of proteins. In general, proteins fold into discrete units that perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of infectious disease, prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.


title: Epigenetics

text: Fungal prions 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 codons, 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.


title: Epigenetics

text: In ciliates such as "Tetrahymena" and "Paramecium", genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.


title: Epigenetics

text: Eukaryotic genomes have numerous nucleosomes. Nucleosome position is not random, and determine the accessibility of DNA to regulatory proteins. Promoters active in different tissues have been shown to have different nucleosome positioning features. This determines differences in gene expression and cell differentiation. It has been shown that at least some nucleosomes are retained in sperm cells (where most but not all histones are replaced by protamines). Thus nucleosome positioning is to some degree inheritable. Recent studies have uncovered connections between nucleosome positioning and other epigenetic factors, such as DNA methylation and hydroxymethylation.


title: Epigenetics

text: Different histone variants are incorporated into specific regions of the genome non-randomly. Their differential biochemical characteristics can affect genome functions via their roles in gene regulation, and maintenance of chromosome structures.


title: Epigenetics

text: The three-dimensional configuration of the genome (the 3D genome) is complex, dynamic and crucial for regulating genomic function and nuclear processes such as DNA replication, transcription and DNA-damage repair.


title: Epigenetics

text: Memory formation and maintenance are due to epigenetic alterations that cause the required dynamic changes in gene transcription that create and renew memory in neurons.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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 IIB 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 mRNA, with peak mRNA transcription at seven to ten minutes after CFC.


title: Epigenetics

text: 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 TET1 to an association, and brings TET1 to about 600 locations on the genome where TET1 can then demethylate and activate the associated genes.


title: Epigenetics

text: The DNA methyltransferases DNMT3A1, DNMT3A2 and DNMT3B can all methylate cytosines (see image this section) at CpG sites 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.


title: Epigenetics

text: 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 CpG sites 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.


title: Epigenetics

text: 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 mRNAs are often packaged into neuronal granules, or messenger RNP, consisting of mRNA, small and large ribosomal subunits, 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 dendrites. 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.


title: Epigenetics

text: In adulthood, changes in the epigenome are important for various higher cognitive functions. Dysregulation of epigenetic mechanisms is implicated in neurodegenerative disorders and diseases. Epigenetic modifications in neurons are dynamic and reversible. Epigenetic regulation impacts neuronal action, affecting learning, memory, and other cognitive processes.


title: Epigenetics

text: Early events, including during embryonic development, can influence development, cognition, and health outcomes through epigenetic mechanisms.


title: Epigenetics

text: Epigenetic mechanisms have been proposed as "a potential molecular mechanism for effects of endogenous hormones on the organization of developing brain circuits".


title: Epigenetics

text: Nutrients could interact with the epigenome to "protect or boost cognitive processes across the lifespan".


title: Epigenetics

text: Epigenetics play a major role in brain aging and age-related cognitive decline, with relevance to life extension.


title: Epigenetics

text: 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.


title: Epigenetics

text: With the axo-ciliary synapse, there is communication between serotonergic axons and antenna-like primary cilia of CA1 pyramidal neurons that alters the neuron's epigenetic state in the nucleus via the signalling distinct from that at the plasma membrane (and longer-term).


title: Epigenetics

text: Developmental epigenetics can be divided into predetermined and probabilistic epigenesis. Predetermined epigenesis is a unidirectional movement from structural development in DNA to the functional maturation of the protein. "Predetermined" here means that development is scripted and predictable. Probabilistic epigenesis on the other hand is a bidirectional structure-function development with experiences and external molding development.


title: Epigenetics

text: 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, morphogens 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 mammals, 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. 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.


title: Epigenetics

text: 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 teratogens, such as diabetic embryopathy, on methylation signatures.


title: Epigenetics

text: 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. 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.


title: Epigenetics

text: Epigenetic mechanisms were a necessary part of the evolutionary origin of cell differentiation. Although epigenetics in multicellular organisms is generally thought to be a mechanism involved in differentiation, with epigenetic patterns "reset" when organisms reproduce, there have been some observations of transgenerational epigenetic inheritance (e.g., the phenomenon of paramutation observed in maize). Although most of these multigenerational epigenetic traits are gradually lost over several generations, the possibility remains that multigenerational epigenetics could be another aspect to evolution and adaptation.


title: Epigenetics

text: 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. 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".


title: Epigenetics

text: Two important ways in which epigenetic inheritance can differ from traditional genetic inheritance, with important consequences for evolution, are:


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: While epigenetics is of fundamental importance in eukaryotes, especially metazoans, it plays a different role in bacteria. Most importantly, eukaryotes use epigenetic mechanisms primarily to regulate gene expression which bacteria rarely do. However, bacteria make widespread use of postreplicative DNA methylation for the epigenetic control of DNA-protein interactions. Bacteria also use DNA adenine methylation (rather than DNA cytosine methylation) as an epigenetic signal. DNA adenine methylation is important in bacteria virulence in organisms such as "Escherichia coli", "Salmonella, Vibrio, Yersinia, Haemophilus", and "Brucella". In "Alphaproteobacteria", methylation of adenine regulates the cell cycle and couples gene transcription to DNA replication. In "Gammaproteobacteria", adenine methylation provides signals for DNA replication, chromosome segregation, mismatch repair, packaging of bacteriophage, transposase activity and regulation of gene expression. There exists a genetic switch controlling "Streptococcus pneumoniae" (the pneumococcus) that allows the bacterium to randomly change its characteristics into six alternative states that could pave the way to improved vaccines. Each form is randomly generated by a phase variable methylation system. The ability of the pneumococcus to cause deadly infections is different in each of these six states. Similar systems exist in other bacterial genera. In Bacillota such as "Clostridioides difficile," adenine methylation regulates sporulation, biofilm formation and host-adaptation.


title: Epigenetics

text: Epigenetics has many and varied potential medical applications. In 2008, the National Institutes of Health announced that $190 million had been earmarked for epigenetics research over the next five years. In announcing the funding, government officials noted that epigenetics has the potential to explain mechanisms of aging, human development, and the origins of cancer, heart disease, mental illness, as well as several other conditions. Some investigators, like Randy Jirtle, Ph.D., of Duke University Medical Center, think epigenetics may ultimately turn out to have a greater role in disease than genetics.


title: Epigenetics

text: Direct comparisons of identical twins constitute an optimal model for interrogating environmental epigenetics. In the case of humans with different environmental exposures, monozygotic (identical) twins were epigenetically indistinguishable during their early years, while older twins had remarkable differences in the overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation. The twin pairs who had spent less of their lifetime together and/or had greater differences in their medical histories were those who showed the largest differences in their levels of 5-methylcytosine DNA and acetylation of histones H3 and H4.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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


title: Epigenetics

text: 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 biomarkers of disease before clinical threshold is reached.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: Some human disorders are associated with genomic imprinting, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their germ cells. The best-known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndrome – both can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father. This is due to the presence of genomic imprinting in the region. Beckwith-Wiedemann syndrome is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.


title: Epigenetics

text: Methyl CpG-binding protein 2 (MeCP2) is a transcriptional regulator that must be phosphorylated before releasing from the BDNF promoter, allowing transcription. Rett syndrome is underlain by mutations in the MeCP2 gene despite no large-scale changes in expression of MeCP2 being found in microarray analyses. BDNF is downregulated in the MECP2 mutant resulting in Rett syndrome, as well as the increase of early neural senescence and accumulation of damaged DNA.


title: Epigenetics

text: In the Överkalix study, paternal (but not maternal) grandsons 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. 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.


title: Epigenetics

text: Epigenetic modifications have given insight into the understanding of the pathophysiology of different disease conditions. Though, they are strongly associated with cancer, their role in other pathological conditions are of equal importance. It appears that the hyperglycaemic environment could imprint such changes at the genomic level, that macrophages are primed towards a pro-inflammatory state and could fail to exhibit any phenotypic alteration towards the pro-healing type. This phenomenon of altered Macrophage Polarization is mostly associated with all the diabetic complications in a clinical set-up. As of 2018, several reports reveal the relevance of different epigenetic modifications with respect to diabetic complications. Sooner or later, with the advancements in biomedical tools, the detection of such biomarkers as prognostic and diagnostic tools in patients could possibly emerge out as alternative approaches. It is noteworthy to mention here that the use of epigenetic modifications as therapeutic targets warrant extensive preclinical as well as clinical evaluation prior to use.


title: Epigenetics

text: The use of beta-lactam antibiotics can alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. Additionally, lithium can impact autophagy of aberrant proteins, and opioid drugs via chronic use can increase the expression of genes associated with addictive phenotypes.


title: Epigenetics

text: In a groundbreaking 2003 report, Caspi and colleagues demonstrated that in a robust cohort of over one-thousand subjects assessed multiple times from preschool to adulthood, subjects who carried one or two copies of the short allele of the serotonin transporter promoter polymorphism exhibited higher rates of adult depression and suicidality when exposed to childhood maltreatment when compared to long allele homozygotes with equal ELS exposure.


title: Epigenetics

text: 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. However, whether and to what extent epigenetic effects can be transmitted across generations remains unclear, particularly in humans.


title: Epigenetics

text: Addiction is a disorder of the brain's reward system which arises through transcriptional and neuroepigenetic mechanisms and occurs over time from chronically high levels of exposure to an addictive stimulus (e.g., morphine, cocaine, sexual intercourse, gambling, etc.). Transgenerational epigenetic inheritance of addictive phenotypes has been noted to occur in preclinical studies. However, robust evidence in support of the persistence of epigenetic effects across multiple generations has yet to be established in humans; for example, an epigenetic effect of prenatal exposure to smoking that is observed in great-grandchildren who had not been exposed.


title: Epigenetics

text: Epigenetic inheritance of depression-related phenotypes has also been reported in a preclinical study. Inheritance of paternal stress-induced traits across generations involved small non-coding RNA signals transmitted via the paternal germline.


title: Epigenetics

text: The two forms of heritable information, namely genetic and epigenetic, are collectively called dual inheritance. Members of the APOBEC/AID family of cytosine deaminases may concurrently influence genetic and epigenetic inheritance using similar molecular mechanisms, and may be a point of crosstalk between these conceptually compartmentalized processes.


title: Epigenetics

text: 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.


title: Epigenetics

text: 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.


title: Epigenetics

text: Epigenetic regulation of gene expression that could be altered or used in epigenome editing are or include mRNA/lncRNA modification, DNA methylation modification and histone modification.


title: Epigenetics

text: As epigenetics is in the early stages of development as a science and is surrounded by sensationalism in the public media, David Gorski and geneticist Adam Rutherford have advised caution against the proliferation of false and pseudoscientific conclusions by new age authors making unfounded suggestions that a person's genes and health can be manipulated by mind control. Misuse of the scientific term by quack authors has produced misinformation among the general public.


title: Fortnite Battle Royale

text: Fortnite Battle Royale is a free-to-play battle royale video game developed and published by Epic Games. It is a companion game to "", a cooperative survival game with construction elements. It was initially released in early access on September 26, 2017, for Windows, macOS, PlayStation 4, and Xbox One, followed by ports for iOS, Android, and Nintendo Switch the following year. Epic dropped the early access label for the game on June 29, 2020. Versions for the PlayStation 5 and Xbox Series X/S were released as launch titles in late 2020.


title: Fortnite Battle Royale

text: The concept of the game is similar to previous games of the genre: 100 players skydive onto an island and scavenge for gear to defend themselves from other players. Players can fight alone, or with up to three other players. As the match progresses, the playable area within the island gradually constricts, giving the players less and less room to work with; outside this safe zone is "the Storm", which inflicts damage on those caught inside it, with the amount of damage growing as the Storm itself does. The last player or team alive wins the match. The main distinction from others in the genre is the game's construction elements, letting players build walls, obstacles, and other structures from collected resources to take cover from incoming fire or give one a strategic view advantage. "Battle Royale" uses a seasonal approach with battle passes to introduce new character customization content in the game, as well as limited-time events, some of which correspond with changes to the game map. Since its initial release, several other game modes have been introduced, including "Battle Lab" and "Party Royale".


title: Fortnite Battle Royale

text: The idea for "Battle Royale" arose following the release of "PlayerUnknown's Battlegrounds" in 2017, a similar battle royale game that was highly successful but noted for its technical flaws. Originally released as part of the early access version of "Save the World", Epic later transitioned the game to a free-to-play model funded by microtransactions. Following its rise in popularity, Epic split the development team, with one focusing on "Battle Royale" and the other on "Save the World".


title: Fortnite Battle Royale

text: "Battle Royale" received positive reviews from critics, who praised its learning curve, gameplay, art style, multiplayer and progression system, but noted its similarity to previous games in the genre. The game quickly rose in popularity following its release, eventually surpassing "Battlegrounds" in overall player count and revenue. Player count had exceeded 350 million by May 2020. The game has gone on to become a cultural phenomenon, with promotion through social media and several celebrities, such as Ninja, Marshmello, and Drake, contributing to the game's popularity, achieving record-high viewership on streaming platforms in the process.


title: Fortnite Battle Royale

text: The main gameplay for "Fortnite Battle Royale" follows the standard format for the battle royale genre. The game normally is played either with each player on their own, or in a squad of two to four players, with up to 100 players participating each round. The round starts with players, weaponless, skydiving from floating buses ("Battle Bus") then deploying a glider onto a region of land. The island's fixed layout includes several landmarks and locations (named in an alliterative fashion, such as "Lazy Lake", "Pleasant Park", and "Retail Row") that are mostly ghost towns during matches, while a random distribution of weapons, shields, and other combat support features can be found by searching chests scattered in buildings and other sites.


title: Fortnite Battle Royale

text: The primary goal is to be the last player or team alive by eliminating or avoiding other players. When playing in solo modes, players are immediately eliminated when they exhaust their health. In squad modes, downed players can crawl around while losing health; they can be eliminated immediately by an opponent or revived by a squadmate to help them up. Initially, when the game launched, eliminated players were out of the match, but starting with updates in April 2019, squadmates can attempt to respawn a downed player at various "Reboot vans" scattered around the map, which are few and far between and in the open, making it a risk to respawn a squadmate. Over time, the game's safe zone (representing the eye of a storm), decreases in size, and players caught outside the zone will take damage. This directs the surviving players into tighter spaces, forcing player encounters. Supply drops will spawn in random locations during a match, providing random weapons and items. Like in the original "" game, "Fortnite Battle Royale" is primarily played in a third-person perspective.


title: Fortnite Battle Royale

text: "Fortnite Battle Royale"s primary distinction from other battle royale games is the building system, which originated from the original "Fortnite" survival game. Nearly all objects in the environment can be destroyed and harvested for materials (wood, stone, and metal), which can then be used to build fortifications of limited durabilities, such as walls, ramps, floors, and roofs, which can be used to help traverse the map, protect the player from gunfire, or slow down progression of other players. Weaker pieces can be destroyed in a few hits, but can be built quickly, while stronger pieces can withstand more damage, but take longer to build. A special Zero Build game mode was introduced in March 2022 which eliminated all building aspects in the Battle Royale mode, and became a permanent secondary mode in the game by April 2022.


title: Fortnite Battle Royale

text: The game is free-to-play, supported by microtransactions that allow players to buy "V-Bucks," the game's internal currency. V-Bucks are also shared with the main "Fortnite: Save the World" game, which offers players the opportunity to earn V-Bucks by completing missions or daily quests. V-Bucks can then be used to buy cosmetic improvements to the player (outfits, pickaxes, gliders, backblings, and emotes). The game is run in chapters with a number of seasons, each season lasting about 10 weeks each. Each season introduces an exclusive set of cosmetic items that can be obtained. These are offered through a dual-track battle pass, which features a number of tiers that players climb through by earning experience through completing in-game objectives, while acquiring cosmetic rewards or other items in the process. Each player has access to the "free" track of the Battle Pass, which offers fewer cosmetics that can be earned by clearing multiple tiers, while players can also purchase the Pass' "premium" track with V-Bucks, which offers more challenges and grants prizes for every tier the player advances. Players can use V-Bucks to purchase tiers as well once they have bought the Battle Pass. Starting in December 2020, Epic added the ""Fortnite" Crew" monthly subscription plan; those on the plan gain access to the latest Battle Pass, a monthly allocation of V-Bucks, and access to exclusive cosmetics only available to subscribers.


title: Fortnite Battle Royale

text: Since release, Epic Games has added more features, such as new weapon and items and makeshift vehicles such as shopping carts and golf carts. Epic is also able to deploy hotfixes to the game to adjust aspects like weapon attributes and distribution, pushing these out in minutes if necessary should they or players discover critical issues or glitches, as well as removing older or not well received items from the game in a process called "vaulting". With the release of the standalone "Fortnite Creative" gameplay mode in December 2018, an area of the "Fortnite Battle Royale" map called "The Block" featured a rotating selection of user-made creations developed in "Creative" mode and approved by Epic. A "Battle Lab" mode was added in December 2019 for players to create their own custom battle royale games. In April 2020, a new "Party Royale" mode was added, taking place on a small map where combat and construction was disabled though non-lethal gameplay items can be acquired like paint guns and vehicles; this map was aimed to be used as a social space, as well as to host in-game events like concerts.


title: Fortnite Battle Royale

text: Prior to September 2019, "Fortnite" did not have specialized matchmaking, outside of platform and regional limits. With an upcoming patch, the game introduced skill-based matchmaking, based on internal metrics that judge a player's skill in the game. Further, with Chapter 2 Season 1, the game will add special matches against computer-controlled bots to help players practice the game.


title: Fortnite Battle Royale

text: Epic has the ability to include limited-time modes (LTM) within the game, which provides Epic with experimental capabilities and gain feedback from players to improve upon. One of its earliest additions was a 50-v-50 mode, placing players randomly on one of two teams and dropping them on opposite sides of the map, giving the two teams time to gather resources, create fortifications, and hunt the other team before the storm moved in. A sandbox Playground LTM was introduced in June 2018, which allows up to four players to explore and build anything anywhere on the battle map, while being able to fight each other and respawn upon defeat until the storm covered the map after an hour and eliminated them all; Epic later made this a permanent mode in the game.


title: Fortnite Battle Royale

text: Epic has stated that they intend to add ranked competitive play in the future. A preliminary competitive mode, Solo Showdown, ran for a limited time starting in May 2018, ranking players by their final placement in matches and rewarding the top-placing competitors with V-Bucks. Epics newest addition to the game, starting out Chapter 3 Season 2, was a temporary change called No-Building. This change removed all building mechanics in game. In exchange Epic added Over-Shield, giving each player 50 shield to start off with that would recharge throughout the game. Epic later turned this change into its own game mode, that would bring the building game mode back.


title: Fortnite Battle Royale

text: Fortnite released a new game mode called Zero Build on March 29, 2022. This game mode initially started out as a temporary change in Chapter 3 Season 2, to the main Battle Royale game mode. This change removed building completely, not allowing any option for a Building Game mode. Epic decided to then make this its own game mode due to its popularity. Epic brought back building on April 2, 2022, allowing for the option of either Building, or Zero Building choice of gameplay. This game mode features no building mechanics, making it less competitive to its successor. Epic added additional 50 Overshield when you start off, giving you the capacity of 250 health/shield total, to help supplement the change in game play. On April 10, 2022, Fortnite released the Zero Build Trials. Signing up for this, and completing the challenges, would allow players to be rewarded with in game rewards. On July 12, 2022, Epic released the first Zero Build Arena mode, a limited time game mode lasting until August 30, 2022. This game was initially released in Trios gameplay, only allowing you to have a total of 3 teammates. The Loot in the Arena mode is identical to the loot found in the Zero Build Mode.


title: Fortnite Battle Royale

text: "Fortnite Battle Royale" has created a larger loose narrative that is exhibited through changes in the game map, which generally correlated to the start and end of the in-game season. For example, in the lead up to the fourth season of the first chapter which started in May 2018, players saw a number of shooting stars cross the skies, followed by a giant comet that neared the ground; upon the start of that season, the comet had hit one of the locations on the map, leaving a giant crater, among other changes. This tied into several new cosmetic skins related to superheroes and super-villains that were available that month. Epic has the ability to create custom events that occur across all game servers simultaneously as well; the first example of such was a countdown leading to a giant rocket's launch in June 2018 which, in the aftermath, left cracks in the skies that have grown since that event.


title: Fortnite Battle Royale

text: The game initially launched without any seasonable schedule, but starting with the release of Chapter 1 Season 2 in December 2017, Epic has provided new content, which includes new cosmetics, new gameplay elements, and changes to the game's map, on a roughly 10-week basis. This also introduced the use of the battle pass for players to obtain some of this new content by completing challenges and gaining experience.


title: Fortnite Battle Royale

text: Shortly after the release of the film "" (2018), Epic ran a Marvel-sponsored event that featured the Infinity Gauntlet that randomly spawned on the map; any player that equipped it became Thanos with added abilities. A second "Avengers"-based mode was released upon the release of "" (2019), where players are randomly split between Avenger and Chitauri armies, seeking out the Infinity Stones or the Infinity Gauntlet. Since then, other promotional content from other commercial properties, including cosmetic items and map features, has been available for limited periods in "Fortnite", typically around the time of premieres or first broadcasts for these works. These commercial properties have included "Ralph Breaks the Internet", "John Wick", "Stranger Things", "Star Wars", "Birds of Prey", "The Matrix", "Cobra Kai", among several others.


title: Fortnite Battle Royale

text: Epic started a regular "Fortnite" Spotlight in-game concert event series in September 2020 using the "Party Royale" game mode, with such concerts from various musicians planned on a weekly basis and free for any player of "Fortnite" to watch. The musician will perform their set in a special studio set up by Epic that will be digitized in game. According to Nate Nanzer, Epic Games head of global partnerships, "We're creating this platform to work with artists — big artists and up-and-coming artists."


title: Fortnite Battle Royale

text: "Fortnite" had first been revealed by Epic Games in 2011, considered to be a combination of "Minecraft" and "Left 4 Dead" as four players would work together to scavenge resources to build fortifications, traps, weapons, and other objects to survive monster attacks. The game ended up with a protracted development period, in part due to both external pressures, with the industry transitioning to a games as a service model, and internal shifts of focus within Epic (including focusing attention on their first free-to-play title "Paragon") to meet the external challenges. During this period, Epic made a deal with Tencent, giving them about 40% of the company in exchange for their support for the games as a service approach as well as ready access to the Chinese video game market. "Fortnite" was confirmed to have a planned 2018 release in June 2017, with a paid early access period starting a month later; the game is planned otherwise as a free-to-play title supported by microtransactions. With release in early access, the game featured its primary gameplay mode, "Save the World", where players in teams up to four would work cooperatively to survive and complete objectives on randomly generated maps.


title: Fortnite Battle Royale

text: During the latter part of "Fortnite"s development, "PlayerUnknown's Battlegrounds" was released in March 2017 on personal computers in early access, and quickly became a popular and successful game, becoming the defining example of the battle royale genre. According to Mustard, the Epic team "loved Battle Royale games like [Battlegrounds]", and explored how they could make a similar mode within "Fortnite"s engine. They kept this mode in a separate development team from the main player versus environment modes for experimentation and as to not throw off the balance in the main game. The Battle Royale mode development was led by Eric Williamson with Zack Estep as production lead. Their goal was to develop the Battle Royale mode quickly from the core "Save the World" mode, putting off any complex features that weren't already in place as to launch the new mode as soon as possible; while they explored such potential ideas, they held off inclusion until after the main mode was launched. The development of the "Battle Royale" mode took about two months starting in July 2017 after the "Save the World" mode had shipped, and was aided by the "Unreal Tournament" team. Key differences for Battle Royale that differed from "Save the World" included a more limited progression for weapons, a small subset of traps, and a smoother, more natural terrain for the maps. They also wanted to aim for games not taking longer than 25 minutes, which led to some decisions of which elements from "Save the World" would not carry over. They had included "Fortnite"s building mechanic for fortifications, not sure how players would use that since the safe zone would continue shrinking, but found quickly that the mechanic helped to distinguish the game from "Battlegrounds" and was used by expert players frequently to win matches, and had since implemented more features to help players with rapidly constructing temporary bases.


title: Fortnite Battle Royale

text: In those two months of development, Epic's plan was to include "Battle Royale" within the paid "Fortnite" game, and originally announced this approach publicly in early September 2017. Only two weeks before it was released did Epic decide to make it a separate free-to-play title, fearing that having it as part of the paid package would slow down the growth of the title. Epic announced this change formally about a week after first announcing "Battle Royale", allowing those that had purchased early access to "Fortnite" in anticipation of this mode to request refunds. This release, which beat out "Battlegrounds" to consoles, caused some concern with "Battlegrounds" developer Bluehole, as they had been working closely with Epic for Unreal engine support in "Battlegrounds", and were worried that "Fortnite" might be able to include planned features to their Battle Royale mode before they could release those in "Battlegrounds".


title: Fortnite Battle Royale

text: With the popularity of "Fortnite Battle Royale" by the start of 2018, Epic split off a separate development team to focus on improvements for this mode. Epic said that their attention to "Fortnite" was causing some of their other games to see lower player populations, leading them to reduce development efforts on these games, particularly "Paragon". By the end of January 2018, Epic announced it was shutting down "Paragon" by April of that year, providing refunds to all players. Similarly, Epic announced it had halted development of the planned free-to-play "Unreal Tournament" game, its team transitioned to "Fortnite", though the game will remain available, playable, and open to end-user modifications. Players on a "Fortnite"-dedicated Reddit forum had expressed concerns that a similar fate could befall the "Save the World" mode of "Fortnite", as externally, the "Save the World" mode has not received the same attention in providing updates and improvements compared to the "Battle Royale" mode since that mode's release.


title: Fortnite Battle Royale

text: According to Mustard, from the start of developing "Fortnite Battle Royale", Epic had been interested in telling a narrative with the game, with a long-term narrative planned out by Mustard, but recognized the challenge when most players were focused on the base mechanics of the title. They decided to make players more as witnesses to the events rather than central characters, allowing the story to be told out through non-player characters that the players may encounter or through the game's additional media. This long-term narrative was designed to be flexible, accounting for both responses from players as well as for cross-promotions that Epic had secured over time, which had connected to the overall concept of a multiverse that is part of this narrative. Incorporating the narrative elements had led the development team to plan out new ways to include them, such as the single-time events across all servers, or specialized single-player missions.


title: Fortnite Battle Royale

text: On June 29, 2020, Epic announced that they considered "Save the World" to no longer be in early access, and as a companion move, eliminated the early access labels from both "Battle Royale" and "Creative" modes.


title: Fortnite Battle Royale

text: Tencent, who is a partial owner of Epic Games, brought "Fortnite Battle Royale" to China in 2018; the company was already involved in supporting "Battlegrounds" in China as well. Tencent planned to spend up to to help promote the game in China, set up eSports tournaments, and fight against copyright infringement and clones of "Fortnite" that have appeared in the country. Epic also worked with Neowiz Games to bring a version of "Fortnite" to South Korea, launched in November 2018.


title: Fortnite Battle Royale

text: Tencent announced in October 2021 that the Chinese version of "Fortnite", which had never left the beta phase and had a number of functional differences from international versions of the game, would be shutting down on November 15, 2021, disallowing new user registration. This move came after new regulations and restrictions made by the Chinese government towards online gaming.


title: Fortnite Battle Royale

text: A release of "Fortnite" for the Nintendo Switch video game console had been rumored in the week prior to the E3 2018 in June 2018. During the Nintendo Direct presentation, Nintendo and Epic Games announced the release of "Fortnite Battle Royale" for the Nintendo Switch, supporting cross-platform play with any other platform except the PlayStation 4; such users are able to carry over their inventory, Battle Pass status, and in-game currency between these platforms through their Epic user account. The game was released on June 12, 2018, the same day as the announcement. It is the first game to support direct voice chat through the Switch console through software provided by Vivox. With the success of the Switch version of "Fortnite", Vivox had made its voice chat software development kit available for other Switch games.


title: Fortnite Battle Royale

text: In March 2018, Epic announced it was making "Fortnite Battle Royale" for Android and iOS mobile devices. The iOS version was released first, and was expected to be followed by the Android version by mid-2018. The beta version for iOS devices launched on March 15, 2018, and opened to all players on April 2, 2018. Epic Games stated that it was not possible to release the Android version with the iOS version simultaneously, and declined to provide a concrete release date for it, because the developers wanted to spend a few months making sure that the game will be compatible with as many Android devices as possible, a task that is not easily accomplished due to the high variety of Android hardware.


title: Fortnite Battle Royale

text: The Android beta version of "Fortnite" was released on August 9, 2018, with a time-exclusivity for selected Samsung mobile devices until August 12, 2018. On August 13, 2018, Epic began sending invites for the Android version to registered users for non-Samsung devices, and by October 11, 2018, the Android client was made available to all without an invite.