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In Biology, epigenetics can be defined as the study of "all heritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA."[1] When a cell undergoes an epigenetic change, it is the phenotype of the cell that is affected. Epigenetic events during embryo development lead to the differentiation of fetal cells. The combined processes of fetal development and cell differentiation are called epigenesis. The term is also sometimes used as a synonym for the closely related topic of chromatin remodeling.
Epigenetics is distinct from genetics, which focuses on how traits are inherited in genes (and associated DNA sequences), because in epigenetic inheritance the DNA sequence itself is not changed.[2].
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, because all of the cells in the body inherit the same DNA sequences (with a few exceptions, such as B cells), 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 and reprogrammed to become totipotent.
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.[3]
Specific epigenetic processes of interest include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, 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.
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.
Several types of epigenetic inheritance systems may play a role in what has become known as cell memory [4]:
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. [5]
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 .
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. There are several layers of regulation of gene expression, one of which is remodelling of chromatin, the complex of DNA and the histone proteins with which it associates. Chromatin remodelling is initiated by one of two things:
While modifications occur throughout the histone sequence, 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. 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. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, causing the DNA to repel itself. 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.
In addition, the positively charged tails of histone proteins from one nucleosome may interact with the histone proteins on a neighboring nucleosome, causing them to pack closely. Lysine acetylation may interfere with these interactions, causing the chromatin structure to open up.
Lysine acetylation may also act 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.
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.
It should be emphasized that differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently than 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.
DNA methylation frequently occurs in repeated sequences, and may help to suppress 'junk DNA'. [6]: 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 [7]. DNMT1 is the most abundant methyltransferase in somatic cells [8], localizes to replication foci [9], has a 10-40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA) [10]. 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 [11]. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation [7] [12].
Because DNA methylation and chromatin remodelling play such a central role in many types of epigenic inheritance, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading, as chromatin remodelling is not always inherited, and not all epigenetic inheritance involves chromatin remodelling.[13]
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.
Somatic epigenetic inheritance, particularly through DNA methylation and chromatin remodelling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate in many different types, which perform different functions, and respond differently to the environment and intercellular signalling. 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 new differentiated cells throughout life, 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. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodelling, it has been hypothesised that plant cells do not have "memories", resetting their gene expression patterns at each cell division using positional information from the environment and surrounding cells to determine their fate.[14]
Epigenetics has many and varied potential medical applications. Congenital genetic disease is well understood, and it is also 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, 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.[15]
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 (eg. 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. The extent to which these phenomena have wider implications for evolutionary theory and philosophy is a matter of debate.
Epigenetic features may play a role in short-term adaptation of species by allowing for reversible phenotype variability. The modification of epigenetic features associated with a region of DNA allows organisms, on a multigenerational timescale, to switch between phenotypes that express and repress that particular gene.[16] As the sequence of the region is not mutated, this change is reversible. It has also been speculated that organisms may take advantage of differential mutation rates associated with epigenetic features to control the mutation rates of particular genes.[16]
As epigenetic forms of heritable variation exist, such as transmission of the secondary structures of prions in yeast, not all hereditary variation in populations follows Mendelian genetics.[17] However, it is not known if these mechanisms produce specific heritable changes in response to the environment. If this does occur, then some instances of evolution would indeed be separate from standard genetic inheritance.[18] However, as these processes appear to be rare and often reversible, their significance to evolutionary biology remains unclear.[19]
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.[20] The most well 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.[21] This is due to the presence of genomic imprinting in the region, a phenomenon in mammals where the father and mother contribute different epigenetic patterns in their germ cells.[22] Beckwith-Wiedemann syndrome is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.
Pembrey and colleagues also observed that the paternal (but not maternal) grandsons of swedish boys who were exposed to famine in the 19th Century were more likely to get diabetes, suggesting that this was a transgenerational epigenetic inheritance[23]
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. [24] [25] 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. [26] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.[27] 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. [28] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms [29].
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.
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.
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