Epigenetics

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Epigenetics is a term in biology used today to refer to features such as and modifications that are stable over rounds of but do not involve changes in the underlying sequence of the organism. These epigenetic changes play a role in the process of , allowing cells to stably maintain different characteristics despite containing the same genomic material. Epigenetic features are inherited when cells divide despite a lack of change in the DNA sequence itself and, although most of these features are considered dynamic over the course of development in multicellular organisms, some epigenetic features show transgenerational inheritance and are inherited from one generation to the next.

Specific epigenetic processes of interest include , , , , , , , , , the progress of , many effects of , regulation of modifications and , and technical limitations affecting and .

Etymology and Definitions

The word "epigenetics" has been associated with many different definitions, and much of the confusion surrounding the use of the word "epigenetics" relates to the fact that it was originally defined to explain phenomena without knowing their molecular basis and with time became narrowly linked to certain phenomena as their molecular basis was discovered.

Originally, the word "epigenetics" (as in "") was coined by in 1942 as a of the words "" and "". Epigenesis is an older word used to describe the differentiation of cells from a totipotent state in embryonic development (used in contrast to "preformationism"). At the time Waddington first used the term "epigenetics" the physical nature of genes and their role in heredity was not known. Epigenetics was Waddington's model of how genes within a multicellular organism interact with their surroundings to produce a . Because all cells within an organism inherit the same DNA sequences, processes crucial for epigenesis rely strongly on epigenetic rather than genetic inheritance. defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."

Another usage of the word "epigenetics" was employed by the psychologist , who developed an "epigenetic theory of human development" which focuses on psycho-social crises.

The modern usage of the word "epigenetic" is more narrow, referring to heritable traits (over rounds of cell division and sometimes transgenerationally) that do not involve changes to the underlying DNA sequence. The Greek "epi-" prefix of the word "epigenetics" implies features that are "on top of" or "in addition to" genetics, and the current usage of the word reflects this—epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.

The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "" and refers to the overall epigenetic state of a cell. The phrase "" has also been adapted—the "" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent 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 or patterns.

Mechanisms

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

DNA methylation and chromatin remodelling

DNA associates with histone proteins to form chromatin.

Because the of a cell or individual is affected by which of its genes are transcribed, heritable can give rise to epigenetic effects. There are several layers of regulation of , one of which is remodelling of chromatin, the complex of DNA and the proteins with which it associates. Chromatin remodelling is initiated by one of two things:

1. of the amino acids that make up histone proteins,
2. or the addition of methyl groups to the DNA, at , to convert cytosine to .

Whereas DNA is not completely stripped of during replication, it is possible that the remaining modified histones may act as templates, initiating identical modification of surrounding new histones after deposition. DNA methylation has a more clear method of propagation through the preferential methylation of hemimethylated symmetric sites by enzymes like Dnmt 1.

Although modifications occur throughout the histone sequence, the unstructured termini of histones (called histone tails) are particularly highly modified. These modifications include , and . Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally correlated with transcriptional competence.

One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because lysine normally has a positive charge on the nitrogen at its end, lysine 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 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 by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive ). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein 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 .

DNA methylation frequently occurs in repeated sequences, and may help to suppress '': Because is chemically very similar to , CpG sites are frequently mutated and become rare in the genome, except at where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent , 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). By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after , and therefore is often referred to as the ‘maintenance' methyltransferase. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.

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. Chromatin remodelling is not always inherited, and not all epigenetic inheritance involves chromatin remodelling.

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, and enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the activity of the they encode. Other epigenetic changes are mediated by the production of different of , or by formation of double-stranded RNA (). 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 , although in some systems where or are important, RNA may spread directly to other cells or nuclei by . A large amount of RNA and protein is contributed to the by the mother during or via , resulting in 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.

Prions

For more details on this topic, see .

are infectious forms of . Proteins generally fold into discrete units which 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 , 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.

are considered epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. and URE3, discovered in in 1965 and 1971, are the two most well 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 which results in suppression of 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 premature stop codon mutations.

Structural inheritance systems

For more details on this topic, see .

In such as and , 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.^[]

Functions and consequences

Development

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, activate or silence genes in an epigenetically heritable fashion, giving cells a "memory". In mammals, most cells terminally differentiate, with only 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.

 Medicine

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 and . These are normal genetic diseases caused by gene deletions, but are unusually common because individuals are essentially because of , and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.

Evolution

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 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. These effects may require enhancements to the standard conceptual framework of .

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 time scale, to switch between phenotypes that express and repress that particular gene. Whereas the DNA 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.

Epigenetic changes have also been observed to occur in response to environmental exposure—for example, mice given some dietary supplements have epigenetic changes affecting expression of the , which affects their fur color, weight, and propensity to develop cancer. Although this change isn't adaptive since the underlying mutation is agouti gene was developed artificially, the observation of epigenetic change occurring in response to environmental factors opens up the possibility of organismal adaptive inheritance—a sort of . Although this remains speculative, if this does occur some instances of evolution would indeed be separate from standard genetic inheritance.

Epigenetic effects in humans

Genomic imprinting and related disorders

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 most well known case of imprinting in human disorders is that of and —both can be produced by the same genetic mutation, , 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 in the region, a phenomenon in mammals where the father and mother contribute different epigenetic patterns in their germ cells. is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.

Transgenerational epigenetic observations

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

Cancer and developmental abnormalities

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

Many teratogens exert specific effects on the fetus by epigenetic mechanisms. While epigenetic effects may preserve the effect of a teratogen such as 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. However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist. for Vidaza(tm), a formulation of (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. In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.

TWO DEFINITIONS:

Epigenetic Code:

The epigenetic code is hypothesized to be a defining code in every eukaryotic cell consisting of the specific epigenetic modification in each cell. It consists of histone modifications defined by the histone code and additional epigenetic modifications such as DNA methylation. The base for the epigenetic code is a system above the genetic code of a single cell, called epigenetics. While in one individual the genetic code in each cell is the same, the epigentic code is tissue and cell specific. "The genetic code is the piano, the epigenetic code the tune."

From Wikipedia, the free encyclopedia

Phenotype:

The genotype-phenotype distinction must be drawn when trying to understand the inheritance of traits and their evolution. The genotype of an organism represents its exact genetic makeup, that is, the particular set of genes it possesses. Two organisms whose genes differ at even one locus (position in their genome) are said to have different genotypes. The transmission of genes from parents to offspring is under the control of precise molecular mechanisms. The discovery of these mechanisms and their manifestations began with Mendel and comprises the field of genetics. The term "genotype" refers, then, to the full hereditary information of an organism. The phenotype of an organism, on the other hand, represents its actual physical properties, such as height, weight, hair color, and so on. It is the organism's physical properties that directly determine its chances of survival and reproductive output. But the inheritance of physical properties occurs only as a secondary consequence of the inheritance of genes. Therefore, to properly understand evolution by natural selection, one must understand the genotype-phenotype distinction.
The mapping of a set of genotypes to a set of phenotypes is sometimes referred to as the genotype-phenotype map.
An organism's genotype is a major (the largest by far for morphology) influencing factor in the development of its phenotype, but it is not the only one. Even two organisms with identical genotypes normally differ in their phenotypes. One experiences this in everyday life with monozygous (i.e. identical) twins. Identical twins share the same genotype, since their genomes are identical; but they never have the same phenotype, although their phenotypes may be very similar. This is apparent in the fact that their mothers and close friends can always tell them apart, even though others might not be able to see the subtle differences. Further, identical twins can be distinguished by their fingerprints, which are never completely identical.
The concept of phenotypic plasticity describes the degree to which an organism's phenotype is determined by its genotype. A high level of plasticity means that environmental factors have a strong influence on the particular phenotype that develops. If there is little plasticity, the phenotype of an organism can be reliably predicted from knowledge of the genotype, regardless of environmental peculiarities during development. An example of high plasticity can be observed in larval newts1: when these larvae sense the presence of predators such as dragonflies, they develop larger heads and tails relative to their body size and display darker pigmentation. Larvae with these traits have a higher chance of survival when exposed to the predators, but grow more slowly than other phenotypes.
In contrast to phenotypic plasticity, the concept of genetic canalization addresses the extent to which an organism's phenotype allows conclusions about its genotype. A phenotype is said to be canalized if mutations (changes in the genome) do not noticeably affect the physical properties of the organism. This means that a canalized phenotype may form from a large variety of different genotypes, in which case it is not possible to exactly predict the genotype from knowledge of the phenotype (i.e. the genotype-phenotype map is not invertible). If canalization is not present, small changes in the genome have an immediate effect on the phenotype that develops.
The terms "genotype" and "phenotype" were created by Wilhelm Johannsen in 1911.

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