Epigenics

Epigenetics is the study of heritable changes in gene function that occur without a change in the sequence of nuclear DNA. It is also the study of the processes involved in the unfolding development of an organism. In both cases, the object of study includes how gene regulatory information that is not expressed in DNA sequences is transmitted from one generation (of cells or organisms) to the next - that is (harking back to the Greek prefix), 'in addition to' the genetic information encoded in the DNA.

Progress in epigenetics
In recent years, there has been rapid progress in understanding epigenetic mechanisms, which include differences in DNA methylation, as well as differences in chromatin structure involving histone modifications. Another possibility involves the genomes of cytoplasmic elements (chloroplasts and mitochondria). Other mechanisms have also been proposed. See below for more detail.

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. Taken to its extreme, this represents the total state of the cell, with the position of each molecule accounted for.

Epigenetic inheritance
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.

Epigenetic inheritance occurs in the development of multicellular organisms: dividing fibroblasts for instance give rise to new fibroblasts (rather than some other cell type) even though their genome is identical to that of all other cells. Quantitative genetic studies in mammals and birds can reveal maternal effects, which is a form of epigenetic transmission, from one generation to the next. This was first observed in maize. Non-genetic paternal effects are rare.

Heritable changes in gene function without DNA change
This includes the study of how environmental factors affecting a parent can result in changes in the way genes are expressed in the offspring.

Processes involved in unfolding development of an organism
This includes gene regulation phenomena such as X chromosome inactivation in mammalian females, and gene silencing within an organism.

Histone acetylation
One way the expression of a gene can be enhanced is through the acetylation on the K9 and K4 lysines of the N-terminus tails of the internal histones of the nucleosome. 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.

Epigenetic inheritance systems
Epigenetic inheritance systems (EISs) allow cells of different phenotype but identical genotype to transmit their phenotype to their offspring, even when the phenotype-inducing stimuli are absent, as is often the case. Three types of EISs may play a role in what has become known as cell memory :


 * 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. 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.
 * 3) Chromatin-marking systems. Proteins or chemical groups that are attached to DNA and modify its activity are called chromatin marks. These marks are copied with the DNA. For example, several cytosines in eukaryotic DNA are methylated (5-methylcytosine). The number and pattern of such methylated cytosines influences the functional state of the gene: low levels of methylation correspond to high potential activity while high levels correspond to low activity. While there are random changes in the methylation pattern, there are also very specific ones, induced by environmental factors. After DNA replication, maintenance DNA methyltransferase make sure the methylation pattern of the parental DNA is copied to the daughter strand.

Comparison to standard theories
Epigenetic variants exhibit spontaneous emergence and reversion. However, they can be induced by the presence of other genetic factors, and some alleles of a gene have been shown to convert the epigenetic status of the same locus on the homologous chromosome. Environmental factors are also known to influence the emergence and reversion of epigenetic factors. This produces the possibility that epigenetic variations might be produced at several loci and in several cells or organisms.

Epigenetic coding and evolution
One question which is now raised is to what extent does epigenetic inheritance play a direct role in evolution? Since the discovery of the structure of DNA in the mid-20th century, biologists have held that the only role the environment plays is in the phase of selection: the environment determines on what grounds selection takes place and what characteristics are necessary for better reproduction opportunities.

For selection to be possible, individuals within a species must differ somewhat. Genes that provide characteristics that allow an organism to survive in its environment become more common over time, while genes that provide characteristics that make the organism less likely to survive become less common over time.

These genetic differences between individuals are thought to arise from random mutations, and in organisms that reproduce sexually, from meiosis. These differences physically exist as changes in the nucleotide base sequence of DNA. The environment can influence these variations. For example, radioactivity randomly changes the base sequence of DNA.

Some forms of epigenetic inheritance may be maintained even through the production of germ cells (meiosis).

A number of experimental studies seem to indicate that epigenetic inheritance plays a part in the evolution of complex organisms. For example, Tremblay et al., have shown that methylation differences between maternally and paternally inherited alleles of the mouse H19 gene are preserved. There are also numerous reports of heritable epigenetic marks in plants.

That epigenetic heredity seems to exist transgenerationally in complex organisms can be explained by allowing for minor epigenetic changes not affecting totipotency. This puts some constraints on the extent to which epigenetic changes can be brought upon DNA, but it allows for EISs to play direct evolutionary roles.

However, in none of these cases does a cell reprogram its DNA to produce genes that increase its ability to survive in a given environment.

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.

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) 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 &ldquo;the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being&rdquo;. However the term "epigenesis" goes back at least to 1896 (see References).

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.

Etymology
The term epigenetics has over time been used in various senses, in part because the Greek prefix 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.