Epigenetics

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In biology, while the subject of genetics focuses on how organisms can inherit traits by inheriting genes from their parent(s), which encode information for cell function as sequences of DNA, epigenetics is sometimes used to refer to additional methods of biological inheritance that do not directly relate to the inheritance of collections of genes. More specifically, it can refer to reversible, heritable changes in gene regulation 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 long-accepted description of embryonic morphogenesis as a gradual process of increasing complexity, in which organs are formed de novo (as opposed to preformationism). However, cellular differentiation processes crucial for epigenesis rely almost entirely on epigenetic rather than genetic inheritance from one cell generation to the next. If this were not so, then somatic cell cloning would be impossible, because a normal organism couldn't be recovered from a differentiated cell nucleus. Because cell differentiation is epigenetic, a somatic cell can be reprogrammed to become totipotent. (One of the few exceptions to this 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—genetically—deleted from the genome. See: Development of B 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, bookmarking, imprinting, 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), the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.

Contents 1 The Epigenome 1.1 Epigenetic inheritance systems 1.1.1 RNA transcripts and their encoded proteins. 1.1.2 Structural inheritance systems 1.1.3 Chromatin-marking systems. 1.1.4 Direct chemical modification of DNA 1.1.5 Prions 1.2 Epigenetic coding and evolution 1.3 Possible epigenetic effects in humans 2 Historical notes 2.1 Etymology 3 See also 4 Further reading 5 External links 6 References

[edit] The Epigenome

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. The epigenetic code is hypothesized to be a defining code in every eukaryotic cell consisting of the specific epigenetic modification in each cell. 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.

[edit] Epigenetic inheritance systems

Several types of epigenetic inheritance systems may play a role in what has become known as cell memory ^[2]:

[edit] RNA transcripts and their encoded proteins.

Sometimes a gene, after being turned on, transcribes a product that (either directly or indirectly) maintains the activity of that gene. For example, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. 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 most 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. ^[3]

[edit] 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^{[citation needed]}.

[edit] 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 transcription 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 transcriptional 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 activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.

[edit] Direct chemical modification of DNA

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'. ^[4]: 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 ^[5]. DNMT1 is the most abundant methyltransferase in somatic cells ^[6], localizes to replication foci ^[7], has a 10-40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA) ^[8]. 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 ^[9]. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation ^{[5] [10]}.

[edit] Prions

Infectious diseases are not typically described as epigenetic regulators, although infection and vertical transmission of viruses such as HIV works in a similar way. However, some prions (such as fungal prions) have been shown to be beneficial, and since they describe the adaptive function of a protein, they are described as an epigenetic inheritance mechanism.

[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 accepts the overriding importance of both natural selection and of the alteration of the DNA genome by random mutation. 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 passed on to subsequent generations of cells. However, the amount of information transmitted epigenetically is limited: it is probably not possible by epigenetic means to create a "half liver/ half intestine" cell that breeds true from one cell generation to the next, nor is it necessarily possible to activate or deactivate the expression of any particular gene by epigenetic means.

The ability of 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. Because only some of the physiological responses of the cell to a stimulus will lead to heritable epigenetic changes, the physiological changes seen in daughter cells do not necessarily need to be the same as those seen in the parental cell. Even if adaptive epigenetic changes can be shown to be inherited from one generation of organisms to the next, they must 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 induce a specific mutation within the genome.

[edit] Possible epigenetic effects in humans

Work by Marcus Pembrey indicates that two distinct genetic conditions -- 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 will develop seems to depend on whether the mutation is inherited from the child's mother or from their father. Since the conventional genome would seem to be the same in either case, this suggests that some inherited traits may depend on information that exists outside 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. ^{[11] [12]} 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. ^[13] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.^[14] 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. ^[15] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms ^[16].

[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 ep?) 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 ep? (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
• Barbara McClintock
• Centromere
• Evolutionary developmental psychology
• Imprinting
• Lamarckism
• Molecular biology
• Maternal effect
• Paramutation
• Prion
• Soft inheritance
• Somatic epitype
• Weismann barrier
• Bookmarking

[edit] Further reading

• 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.
• 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)

[edit] External links

• DNA Is Not Destiny - Discover Magazine cover story
• The Scientist article (Epigenetics)

[edit] References

v • d • e 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	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