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Epigenetics is the study of epigenetic inheritance, a set of reversible heritable changes in gene function or other cell phenotype that occur without a change in DNA sequence (genotype). These changes may be induced spontaneously, in response to environmental factors, or in response to the presence of a particular allele, even if it is absent from subsequent generations. Epigenetics is distinct from epigenesis, which is the theory of embryonic morphogenesis as a gradual process of increasing complexity, in which organs are formed de novo (as opposed to preformationism), and the subsequent description and study of this process. However, the cellular differentiation processes crucial for epigenesis rely almost entirely on epigenetic rather than genetic inheritance from one cell generation to the next, as evidenced by the feasibility of somatic cell cloning, in which a normal organism can be recovered from a differentiated cell nucleus which is reprogrammed to become totipotent. (One of the few exceptions is the rearrangement of genes in the adaptive immune system - an organism cloned from a memory B cell would lack the ability to generate a full range of immunoglobulins because a portion of the DNA has been irreversibly deleted in these cells.) Epigenetics includes the study of effects that are inherited from one cell generation to the next whether these occur in embryonic morphogenesis, regeneration, normal turnover of cells, tumors, cell culture, or the replication of single celled organisms. Recently, there has been increasing interest in the idea that some forms of epigenetic inheritance may be maintained even through the production of germ cells (meiosis), and therefore may endure from one generation to the next in multicellular organisms.^[1]

Specific epigenetic processes of interest include paramutation, imprinting (such as mouse H19^[2]), gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects (paternal effects are rare, since much less non-genomic material is transmitted by sperm), epigenetic carcinogens, possible teratogen effects on males or second generation infants, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning

Contents 1 The epigenome: epigenetic inheritance systems 1.1 Epigenetic coding and evolution 1.2 Possible epigenetic effects in humans 2 Historical notes 2.1 Etymology 3 See also 4 External links 5 References

[edit] The epigenome: epigenetic inheritance systems

The epigenome is the overall epigenetic state of a cell. As one embryo can generate a multitude of cell fates during development, one genome could be said to give rise to many epigenomes. Taken to its extreme, this represents the total state of the cell, with the position of each molecule accounted for; 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. Several types of epigenetic inheritance systems may play a role in what has become known as cell memory ^[3]:

1. Steady-state systems. Some metabolic patterns are self-perpetuating. Sometimes a gene, after being turned on, transcribes a product (either directly or indirectly) that maintains the activity of that gene. (See also: Hnf4, MyoD) 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. Also, diffusion of the gene's product to other cells can make the (heritable) characteristic spread.
2. Structural inheritance systems. 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 ^[2].
3. Chromatin-marking systems. Since the phenotype of a cell or individual is affected by which of its genes it transcribes, heritable transcription states can give rise to epigenetic effects. One way the expression of a gene can be heritably regulated is through the modification of the amino acids that make up histone proteins. Since DNA is not completely stripped of nucleosomes during replication, the remaining modified histones are thought to template identical modification of surrounding new histones after deposition. It should be noted, though, that not all histone modifications are inherited from one generation to another.
   The unstructured termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation and ubiquitylation. 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 correlated with transcriptional competence.
   One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. It states that since lysine normally has a positive charge on the nitrogen at its end, it can bind the negatively charged phosphates of the DNA backbone and prevent them from repelling each other. When the charge is neutralized, the DNA can fold tightly, thus preventing access to the DNA by the transcriptional machinery. When an acetyl group is added to the +NH2 of the lysine, it removes the positive charge and causes the DNA to repel itself and not fold up so tightly. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA, thus opening it up and exposing it to enzymes like RNA polymerase so transcription of the gene can occur.
   On the other hand, many scientists believe that lysine acetylation acts as a beacon to recruit other activating chromatin modifying enzymes (and basal transciption machinery as well). Indeed, the bromodomain - a protein segment (domain) that specifically binds acetyl-lysine - is found in many enzymes that help activate transcription including the SWI/SNF complex (on the protein polybromo). It may be that acetylation acts in this and the previous way to aid in transciptional activation.
   However, the idea that modifications act as docking modules for related factors is borne out with histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin). 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 the biophysical model for acetylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional actication. Tri-methylation in this case would introduce a fixed positive charge on the tail.
4. Direct chemical modification of DNA also affects transcriptional output. Notably, many cytosines in eukaryotic DNA are methylated to 5-methylcytosine, particularly at CpG sites. The number and pattern of such methylated cytosines influences the functional state of associated genes: low levels of methylation correspond to high potential activity while high levels correspond to low activity. DNA methylation frequently occurs in repeated sequences, and may help to suppress 'junk DNA'.[1] Because 5-methylcytosine is chemically very similar 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 (Li et al., 1992). DNMT1 is the most abundant methyltransferase in somatic cells (Robertson et al., 1999), localizes to replication foci (Leonhardt et al., 1992), has a 10-40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA) (Chuang et al., 1997). 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 (Robertson and Wolffe, 2000). DNMT1 is essential for proper embryonic development, imprinting and X-inactivation (Li et al., 1992; Li et al., 1993).

[edit] Epigenetic coding and evolution

Epigenetics is reminiscent of earlier theories of the inheritance of acquired characters (Lamarckism or Darwin's speculations on pangenesis). However, unlike earlier theories, epigenetics does not dispute the importance of the genome or of natural selection. For example, once a portion of the foregut is exposed to secretions from cardiogenic mesoderm, its cells become liver cells, and this acquired characteristic is then maintained by subsequent generations of cells. However, the amount of information transmitted epigenetically is limited: it may not be possible to create a "half liver, half intestine" cell that breeds true from one generation to the next, nor to deactivate the expression of any chosen gene by epigenetic means, nor to prevent cells from taking on different roles as they migrate from one zone of the liver to the next. The ability for a cell to take on and maintain a "liver" identity reflects a long history of natural selection to make that an inducible and stable phenotype. If any epigenetic information persists between generations, it may only affect only a portion of the regulatory response, so the change observed in the offspring of parents exposed to a stimulus may not be the same as that observed in their parents. Even if adaptive epigenetic changes can be shown to be inherited from one generation to the next, they would still arise as regulatory mechanisms encoded by the genome and in response to natural selection, and they will likely be transient and eventually reversible unless they can induce specific mutation of the genome.

[edit] Possible epigenetic effects in humans

Work by Marcus Pembrey indicates that both Angelman syndrome and Prader-Willi syndrome appear to be produced by the same genetic mutation, chromosome 15q partial deletion, and that the particular syndrome that a child has seems to depend on whether the mutation was inherited from the child's mother or father. This suggests that inherited aspects of development may depend on more than just the "conventional" genome.

A variety of compounds are considered as epigenetic carcinogens - they result in an increased incidence of tumors, but they do not show mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include diethylstilbestrol, arsenite, hexachlorobenzene, and nickel compounds.

Many teratogens exert specific effects on the fetus by epigenetic mechanisms.[2][3] While epigenetic effects may preserve the effect of a teratogen such as diethylstilbestrol throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence.[4] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.[5] FDA label information for Vidaza(tm), a formulation of 5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development. In rats, endocrine differences were observed in offspring of males exposed to morphine. [6] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms [7].

[edit] Historical notes

Some biologists at one time believed that genetics, which seemed to postulate a one-to-one correspondence between genotype and phenotype, could not explain cell differentiation. They developed a theory that each undifferentiated cell underwent a crisis that determined its fate, which was not inherent in its genes, and was therefore (borrowing from the Greek επι) epigenetic.

The psychologist Erik Erikson developed an epigenetic theory of human development which focuses on psycho-social crises. In Erikson's view, each individual goes through several developmental stages, the transition between each of which is marked by a crisis. According to the theory, although the stages are largely predetermined by genetics, the manner in which the crises are resolved is not; by analogy with the epigenetic theory of cell differentiation, the process was said to be epigenetic.

The biologist C.H. Waddington is sometimes credited with coining the term epigenetics in 1942, when he defined it as “the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being”. However the term "epigenesis" has been used since the early eighteenth century. (see also Pierre Louis Maupertuis)

Epigenetic inheritance is the transmission of information from a cell or multicellular organism to its descendants without that information being encoded in the nucleotide sequence of the gene. This information, rather, can be stored as methylation on a nucleotide base, without changing the base sequence. The study of epigenetic inheritance is known as epigenetics.

[edit] Etymology

The term epigenetics has over time been used in various senses, in part because the Greek prefix επι (epi-) has at least six meanings in English (including 'on', 'after' and 'in addition'), but also because various theories of epigenetic development, inheritance, and evolution have been proposed.

[edit] See also

• Baldwinian evolution
• Evolutionary developmental psychology
• Molecular biology
• Lamarckism
• Centromere
• Imprinting
• Maternal effect
• Paramutation
• Prion
• Weismann barrier
• Soft inheritance
• Barbara McClintock

[edit] External links

• The Epigenome Network of Excellence (NoE)
• Public science website for the Epigenome NoE
• Human Epigenome Consortium
• BBC Horizon 2005 "The Ghost In Your Genes" documentary on Epigenetics.
• Code 2 article (lifestyles & gene activation)
• Epigenetics and its applications
• Epigenetics News
• Epigenetic Centre for Protocol and Information Resources
• Epigentek, Largest Manufacturer of Epigenetic Research Products

[edit] References

1. ↑ R.A. Waterland, R.L. Jirtle, "Transposable elements: Targets for early nutritional effects on epigenetic gene regulation", Molecular and Cellular Biology 2003 August 1;23(15):5293-5300.
2. ↑ ^{2.0 2.1} K.D. Tremblay; J.R. Saam; R.S. Ingram; S.M. Tilghman and M.S. Bartolomei; A paternal-specific methylation imprint marks the alleles of the mouse H19 gene. Nature Genet. 9: 407-413 (1995)
3. ↑ E. Jablonka; M. Lachmann and M.J. Lamb; Evidence, mechanisms and models for the inheritance of acquired characteristics, J. Theoret. Biol. 158: 245-268 (1992)

• Oskar Hertwig, 1849-1922. Biological problem of today: preformation or epigenesis? The basis of a theory of organic development. W. Heinemann: London, 1896.
• R. Jaenisch and A. Bird (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33 (Suppl) 245-254.
• Joshua Lederberg, "The Meaning of Epigenetics", The Scientist 15(18):6, Sep. 17, 2001.
• R. J. Sims III, K. Nishioka and D. Reinberg (2003) Histone lysine methylation: a signature for chromatin function. Trends Genet. 19, 629-637.
• B. D. Strahl and C. D. Allis (2000) The language of covalent histone modifications. Nature 403, 41-45.
• C.H. Waddington (1942), "The epigenotype". Endeavour 1, 18–20.
• R.A. Waterland, R.L. Jirtle, "Transposable elements: Targets for early nutritional effects on epigenetic gene regulation", Molecular and Cellular Biology 2003 August 1;23(15):5293-5300.
• B. McClintock (1978) Mechanisms that Rapidly Reorganize the Genome. Stadler Symposium vol 10:25-48
• G.W. Grimes; K.J. Aufderheide; Cellular Aspects of Pattern Formation: the Problem of Assembly. Monographs in Developmental Biology, Vol. 22. Karger, Basel (1991)
• Li E, Bestor TH, and Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69 , 915-926 (1992)
• Li E, Beard C, and Jaenisch R. Role for DNA methylation in genomic imprinting. Nature 366 , 362-365 (1993)
• Robertson KD, Uzyolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, and Jones PA. The human DNA methyltransferases (DNMTs) 1, 3a, 3b: Coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res. 27 , 2291-2298 (1999)
• Leonhardt H, Page A, Weier H, and Bestor TH. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71 , 865-873 (1992)
• Chuang, L. Human DNA-(cytosine-5) methyltransferase-PCNA complex is target for p21 Waf1 . Science 277 , 1996-2000 (1997)
• Robertson, K.D. and Wolffe, A.P. DNA methylation in health and disease. Nature Rev. Genet. 1 , 11-19 (2000)

edit The development of phenotype
Key concepts: Genotype-phenotype distinction | Norms of reaction | Gene-environment interaction | Heritability | Quantitative genetics
Genetic architecture: Dominance relationship | Epistasis | Polygenic inheritance | Pleiotropy | Plasticity | Canalisation | Fitness landscape
Non-genetic influences: Epigenetic inheritance | Epigenetics | Maternal effect | dual inheritance theory
Developmental architecture: Segmentation | Modularity
Evolution of genetic systems: Evolvability | Mutational robustness | Evolution of sex
Influential figures: C. H. Waddington | Richard Lewontin
Debates: Nature versus nurture
List of evolutionary biology topics

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