DNA methylation

Epigenetics [ep-uh-juh-net-iks] is the study of changes in gene activity which are not caused by changes in the DNA sequence. More specifically, epigenetics is the study of gene expression, the way genes bring about their phenotypic effects (observable characteristics or traits).

Gene expression is the process by which the heritable information in a gene, the sequence of DNA base pairs, is made into a functional gene product, such as protein or RNA. The basic idea is that DNA is ‘transcribed’ into RNA, which is then ‘translated’ into proteins (which make many of the structures and all the enzymes in a cell or organism).

 Several steps in the gene expression process may be modulated (tuned). This includes both the transcription and translation stages, and the final folded state of a protein. Gene regulation (mechanisms used by cells to increase or decrease the production of specific gene products) switches genes on and off, and so controls cell differentiation, and morphogenesis (the biological process that causes an organism to develop its shape). Gene regulation may also serve as a basis for evolutionary change: control of the timing, location, and amount of gene expression can have a profound effect on the development of the organism. A well-known example is that of the honey bee. Larvae that are fed with a pollen and nectar diet develop into worker bees, while those fed royal jelly develop into queens, growing larger and with different morphology.

The expression of a gene may vary a lot in different tissues. This is called pleiotropism, a widespread phenomenon in genetics. In pleiotropism, a single gene affects a number of phenotypic traits in the same organism. These pleiotropic effects often seem to be unrelated to each other. The underlying mechanism is that the same gene is activated in several different tissues, producing apparently different effects. It follows that the phenomenon must be extremely common, since most genes will have effects in more than one tissue. Changes in gene activity may persist for the remainder of the cell’s life and may also last for many generations of cells, through cell divisions. However, there is no change in the underlying DNA sequence of the organism. Instead, non-hereditary factors cause the organism’s genes to behave (express themselves) differently.

The best example of epigenetic changes in eukaryotes is the process of cell differentiation. During morphogenesis, generalized stem cells become the cell lines of the embryo which in turn become fully differentiated cells. In other words, a single fertilized egg cell – the zygote – divides and changes into all the many cell types: neurons, muscle cells, epithelium, blood vessels etc. As the embryo develops, some genes get switched on, while others are switched off or moderated (gene regulation). There are many molecules inside the cell nucleus which do the job of adjusting the genes’ output.

DNA and histones (proteins which package DNA into structural units called nucleosomes) make up what is called chromatin (the complex combination of DNA and proteins that makes up chromosomes). Epigenetic modifications to the chromatin are copied during cell division. This produces a line of cells, all of which are alike. This is called a tissue. Sexual reproduction requires meiosis (a special type of cell division, which unlike mitosis, the way normal body cells divide, results in cells that only have half the usual number of chromosomes, one from each pair), which cancels epigenetic changes, and resets the genome to its baseline state, so the process unfolds in each new generation. There are some exceptions to this rule, but none of these exceptions involve changes to DNA base pair sequences. The epigenetic process is different from mutations of the DNA. Genetic mutations change the primary DNA sequence, and mutations can happen in any cell. However, only mutations in cells involved in reproduction can affect the offspring.

Another major component to epigenics is DNA methylation: the addition of a methyl group to various points on a DNA chain. This modification can be inherited through cell division. DNA methylation is a crucial part of normal organismal development and cellular differentiation in higher organisms. DNA methylation stably alters the gene expression pattern in cells such that cells can ‘remember where they have been’ or decrease gene expression; for example, cells programmed to be pancreatic islets during embryonic development remain pancreatic islets throughout the life of the organism without continuing signals telling them that they need to remain islets. DNA methylation is typically removed during zygote formation and re-established through successive cell divisions during development. In addition, DNA methylation suppresses the expression of viral genes and other deleterious elements that have been incorporated into the genome of the host over time. DNA methylation also forms the basis of chromatin structure, which enables cells to form the myriad characteristics necessary for multicellular life from a single immutable sequence of DNA. DNA methylation also plays a crucial role in the development of nearly all types of cancer.

There exist several definitions of epigenetics, and as a result, there are disagreements as to what epigenetics should mean. Epigenetics (as in ‘epigenetic landscape’) was coined by developmental biologist C. H. Waddington in 1942 as a portmanteau of the words ‘genetics’ and ‘epigenesis.’ Epigenesis is an old word that has more recently been used to describe the differentiation of cells from their initial totipotent state in embryonic development (at their highest potential to differentiate into different cell types). When Waddington coined the term the physical nature of genes and their role in heredity was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype. British molecular biologist Robin Holliday defined epigenetics as ‘the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms.’ Thus epigenetic can be used to describe anything other than DNA sequence that influences the development of an organism.

The more recent usage of the word in science has a stricter definition. It is, as defined by geneticist Arthur Riggs and colleagues, ‘the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence.’ The Greek prefix ‘epi-‘ in epigenetics implies features that are ‘on top of’ or ‘in addition to’ genetics; thus epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance. The term ‘epigenetics,’ however, has been used to describe processes which haven’t been demonstrated to be heritable such as histone modification, there are therefore attempts to redefine it in broader terms that would avoid the constraints of requiring heritability. For example, geneticist 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 (misshapen proteins) unless they impinge on chromosome function. Such redefinitions however are not universally accepted and are still subject to dispute.

The similarity of the word to ‘genetics’ has generated many parallel usages. The ‘epigenome’ is a parallel to the word ‘genome,’ and refers to the overall epigenetic state of a cell. 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. 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. The psychologist Erik Erikson used the term epigenetic in his book ‘Identity: Youth and Crisis’ (1968). Erikson writes that the epigenetic principle is where ‘anything that grows has a ground plan, and that out of this ground plan, the parts arise, each part having its time of special ascendancy, until all parts have arisen to form a functioning whole.’ That usage, however, is of primarily historical interest.

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 a misshapen 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.

Somatic epigenetic inheritance through epigenetic modifications, particularly through DNA methylation and chromatin remodeling, 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 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 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.

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. A sequestered germ line or Weismann barrier is specific to animals, and epigenetic inheritance is expected to be far more common in plants and microbes. These effects may require enhancements to the standard conceptual framework of the modern evolutionary synthesis.

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. When 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. Evolutionary 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. 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 agouti gene, which affects their fur color, weight, and propensity to develop cancer.

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. In the Överkalix study, Marcus Pembrey and colleagues observed that the 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.

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). Many teratogens (birth defect-causing agents) exert specific effects on the fetus by epigenetic mechanisms. While epigenetic effects may preserve the effect of a teratogen 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.

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