Epigenetics
Encyclopedia
In biology
, and specifically genetics
, epigenetics is the study of heritable changes in gene expression
or cellular phenotype caused by mechanisms other than changes in the underlying DNA
sequence – hence the name epi- (Greek: επί- over, above, outer) -genetics
. It refers to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such changes might be DNA methylation
or histone deacetylation
, both of which serve to suppress gene expression without altering the sequence of the silenced genes. In 2011, it was demonstrated that the methylation
of mRNA
has a critical role in human energy homeostasis
. This opened the field of RNA epigenetics.
These changes may remain through cell
division
s for the remainder of the cell's life and may also last for multiple generations. However, there is no change in the underlying DNA
sequence of the organism; instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.
One example of epigenetic changes in eukaryotic biology is the process of cellular differentiation
. During morphogenesis
, totipotent stem cells become the various pluripotent cell lines of the embryo
which in turn become fully differentiated cells. In other words, a single fertilized egg cell – the zygote
– changes into the many cell types including neurons, muscle cells, epithelium, endothelium of blood vessels etc. as it continues to divide
. It does so by activating some genes while inhibiting others.
One example of epigenetic change that can be found in animals can be seen in rat pups. It has been found that when rat mothers give birth to their pups they will clean and groom them, which is a form of tactile stimulation. However it seems that not all mothers groom their young the same way, thus causing us to place them into two groups: High LG mothers and Low LG mothers. The high LG mothers groom and lick their young at a much more increased rate than the low LG mothers. As a result it was found that the pups of high LG mothers were healthier, grew at a good rate, and were all around much better off than the pups raised by low LG mothers. Therefore it seems that the way rat pups develop is not exactly genetic, but epigenetic. Further research discovered that the licking of the mother triggers the hippocampus in the rat pup, which then stimulatea the hypothalamus which releases CRF that stimulates the pituitary to release ACTH which finally causes the adrenal to release glucocoritchoids. This cascade of events all caused by the licking and grooming of the mother causes that pup to have decreased CRF expression in the hypothalamus, reduced ACTH and glucocortichoid responses to acute stress, and significantly increased glucocortichoid receptor expression.
") was coined by C. H. Waddington
in 1942 as a portmanteau of the words genetics
and epigenesis
. Epigenesis is an old word which has more recently been used (see preformationism
for historical background) to describe the differentiation of cells from their initial totipotent state in embryonic development. 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
.
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 modern usage of the word in scientific discourse 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 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 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. 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
patterns.
The psychologist Erik Erikson
used the term epigenetic in his theory of psychosocial development. That usage, however, is of primarily historical interest.
. Additionally, the chromatin
proteins associated with DNA may be activated or silenced. This accounts for why the differentiated cells in a multi-cellular organism express only the genes that are necessary for their own activity. Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic changes are inherited from one generation to the next. This raises the question of whether or not epigenetic changes in an organism can alter the basic structure of its DNA (see Evolution, below), a form of Lamarckism
.
Specific epigenetic processes include paramutation
, bookmarking
, imprinting
, gene silencing
, X chromosome inactivation
, position effect
, reprogramming
, transvection
, maternal effect
s, the progress of carcinogenesis
, many effects of teratogens, regulation of histone
modifications and heterochromatin
, and technical limitations affecting parthenogenesis
and cloning
.
Epigenetic research uses a wide range of molecular biologic techniques to further our understanding of epigenetic phenomena, including chromatin immunoprecipitation
(together with its large-scale variants ChIP-on-chip
and ChIP-Seq), fluorescent in situ hybridization
, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification (DamID
) and bisulfite sequencing
. Furthermore, the use of bioinformatic methods is playing an increasing role (computational epigenetics
).
Because the phenotype
of a cell or individual is affected by which of its genes are transcribed, heritable transcription states
can give rise to epigenetic effects. There are several layers of regulation of gene expression
. One way that genes are regulated is through the remodeling of chromatin. Chromatin is the complex of DNA and the histone
proteins with which it associates. Histone proteins are little spheres that DNA wraps around. If the way that DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:
The way that the cells stay differentiated in the case of DNA methylation is clearer to us than it is in the case of histone shape. Basically, certain enzymes (such as DNMT1
) have a higher affinity for the methylated cytosine. If this enzyme reaches a "hemimethylated" portion of DNA (where methylcytosine is in only one of the two DNA strands) the enzyme will methylate the other half.
Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation
, methylation
, ubiquitylation, phosphorylation
and sumoylation. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysine
s 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 it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, thus loosening the DNA from the histone. When this occurs, complexes like SWI/SNF
and other transcriptional factors can bind to the DNA and allow transcription to occur. This is the "cis" model of epigenetic function. In other words, changes to the histone tails have a direct affect on the DNA itself.
Another model of epigenetic function is the "trans" model. In this model changes to the histone tails act indirectly on the DNA. For example, lysine acetylation may create a binding site for chromatin modifying enzymes (and basal transcription machinery as well). This Chromatin Remodeler can then cause changes to the state of the chromatin. 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 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 this 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 has been shown that the histone lysine methyltransferase (KMT) is responsible for this methylation activity in the pattern of histones H3 & H4. This enzyme utilizes a catalytically active site called the SET domain (Suppressor of variegation, Enhancer of zeste, Trithorax). The SET domain is a 130-amino acid sequence involved in modulating gene activities. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone.
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 helps to suppress the expression and mobility of 'transposable elements': 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 methyltransferase
s, 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 DNA replication
, and therefore is often referred to as the ‘maintenance' methyltransferase. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.
Histones H3 and H4 can also be manipulated through demethylation using histone lysine demethylase (KDM). This recently identified enzyme has a catalytically active site called the Jumonji domain (JmjC). The demethylation occurs when JmjC utilizes multiple cofactors to hydroxylate the methyl group, thereby removing it. JmjC is capable of demethylating mono-, di-, and tri-methylated substrates. .
Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of states of larger chromosomal regions are often thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. A simplified stochastic model for this type of epigenetics is found
here
.
Because DNA methylation and chromatin remodeling 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 remodeling is not always inherited, and not all epigenetic inheritance involves chromatin remodeling.
It has been suggested that the histone code
could be mediated by the effect of small RNAs. The recent discovery and characterization of a vast array of small (21- to 26-nt), non-coding RNAs suggests that there is an RNA component, possibly involved in epigenetic gene regulation. Small interfering RNA
s can modulate transcriptional gene expression via epigenetic modulation of targeted promoters.
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. RNA signalling includes differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. 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 cell
s, 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.
s are infectious forms of protein
s. 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 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.
Fungal prions are considered epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast
in 1965 and 1971, are the two best 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 nonsense mutation
s 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.
s 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.
s 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 mammal
s, 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 remodeling
, 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.
and Prader-Willi syndrome
. These are normal genetic diseases caused by gene deletions or inactivation of the genes, 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.
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. Interestingly, recent analysis have suggested that members of the APOBEC/AID family of cytosine deaminases are capable of simultaneously mediating genetic and epigenetic inheritance using similar molecular mechanisms.
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 meaning 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.
More than 100 cases of transgenerational epigenetic inheritance phenomena have been reported in a wide range of organisms, including prokaryotes, plants, and animals.
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. This is due to the presence of genomic imprinting in the region. Beckwith-Wiedemann syndrome
is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.
Marcus Pembrey and colleagues also observed in the Överkalix study
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.
, arsenite
, hexachlorobenzene
, and nickel
compounds.
Many teratogens exert specific effects on the fetus by epigenetic mechanisms. 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. However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist. 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. In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.
Recent studies have shown that the Mixed Lineage Leukemia
(MLL) gene causes leukemia
by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control.
Other investigations have concluded that alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer. Gene expression in the prostate can be modulated by nutrition and lifestyle changes.
In 2008, the National Institutes of Health announced that $190 million had been earmarked for epigenetics research over the next five years. In announcing the funding, government officials noted that epigenetics has the potential to explain mechanisms of aging, human development, and the origins of cancer, heart disease, mental illness, as well as several other conditions. Some investigators, like Randy Jirtle, PhD, of Duke University Medical Center, think epigenetics may ultimately turn out to have a greater role in disease than genetics.
is an important regulator of gene transcription and a large body of evidence has demonstrated that aberrant DNA methylation is associated with unscheduled gene silencing, and the genes with high levels of 5-methylcytosine in their promoter region are transcriptionally silent. DNA methylation is essential during embryonic development, and in somatic cells, patterns of DNA methylation are generally transmitted to daughter cells with a high fidelity. Aberrant DNA methylation patterns have been associated with a large number of human malignancies and found in two distinct forms: hypermethylation and hypomethylation compared to normal tissue. Hypermethylation is one of the major epigenetic modifications that repress transcription via promoter region of tumour suppressor genes. Hypermethylation typically occurs at CpG islands in the promoter region and is associated with gene inactivation. Global hypomethylation has also been implicated in the development and progression of cancer through different mechanisms.
variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many nuclear processes by altering chromatin
structure. One of the key H2A variants, H2A.X, marks DNA damage, facilitating the recruitment of DNA repair proteins to restore genomic integrity. Another variant, H2A.Z, plays an important role in both gene activation and repression. A high level of H2A.Z expression is ubiquitously detected in many cancers and is significantly associated with cellular proliferation and genomic instability.
and chemotherapy
, or could enhance the effects of these current treatments. It has been shown that the epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones directly affects the formation and progression of cancer Epigenetics also has the factor of reversibility, a characteristic that other cancer treatments do not offer.
Drug development has mainly focused on Histone Acetyltransferase (HAT) and Histone Deacetylase (HDAC), including the introduction of the new pharmaceutical Vorinostat
, a HDAC inhibitor, to the market. HDAC specifically has been shown to play an integral role in the progression of oral squamous cancer
Current front-runner candidates for new drug targets are Histone Lysine Methyltransferases
(KMT) and Protein Arginine Methyltransferases (PRMT).
methylation (rather than DNA cytosine
methylation) as an epigenetic signal. DNA adenine methylation is important in bacteria virulence in organisms such as Escherichia coli
, Salmonella
, Vibrio
, Yersinia
, Haemophilus
, and Brucella
. In Alphaproteobacteria
, methylation of adenine regulates the cell cycle and couples gene transcription to DNA replication. In Gammaproteobacteria
, adenine methylation provides signals for DNA replication, chromosome segregation, mismatch repair, packaging of bacteriophage, transposase activity and regulation of gene expression.
The filamentous fungus Neurospora crassa is a prominent model system for understanding the control and function of cytosine methylation. In this organisms, DNA methylation is associated with relics of a genome defense system called RIP (repeat-induced point mutation) and silences gene expression by inhibiting transcription elongation.
The yeast
prion
PSI is generated by a conformational change of a translation termination factor, which is then inherited by daughter cells. This can provide a survival advantage under adverse conditions. This is an example of epigenetic regulation enabling unicellular organisms to respond rapidly to environmental stress. Prions can be viewed as epigenetic agents capable of inducing a phenotypic change without modification of the genome.
Biology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...
, and specifically genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
, epigenetics is the study of heritable changes in gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
or cellular phenotype caused by mechanisms other than changes in the underlying DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
sequence – hence the name epi- (Greek: επί- over, above, outer) -genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
. It refers to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such changes might be DNA methylation
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
or histone deacetylation
Histone acetylation and deacetylation
In histone acetylation and deacetylation, the histones are acetylated and deacetylated on lysine residues in the N-terminal tail and on the surface of the nucleosome core as part of gene regulation. These reactions are typically catalyzed by enzymes with "histone acetyltransferase" or "histone...
, both of which serve to suppress gene expression without altering the sequence of the silenced genes. In 2011, it was demonstrated that the methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
of mRNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
has a critical role in human energy homeostasis
Energy balance (biology)
In biology, energy balance is the biological homeostasis of energy in living systems. It is measured with the following equation: Energy intake = internal heat produced + external work + storage. It is also an aspect of bioenergetics, concerning energy flow through living systems.It generally uses...
. This opened the field of RNA epigenetics.
These changes may remain through cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
division
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
s for the remainder of the cell's life and may also last for multiple generations. However, there is no change in the underlying DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
sequence of the organism; instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.
One example of epigenetic changes in eukaryotic biology is the process of cellular differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
. During morphogenesis
Morphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
, totipotent stem cells become the various pluripotent cell lines of the embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
which in turn become fully differentiated cells. In other words, a single fertilized egg cell – the zygote
Zygote
A zygote , or zygocyte, is the initial cell formed when two gamete cells are joined by means of sexual reproduction. In multicellular organisms, it is the earliest developmental stage of the embryo...
– changes into the many cell types including neurons, muscle cells, epithelium, endothelium of blood vessels etc. as it continues to divide
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
. It does so by activating some genes while inhibiting others.
One example of epigenetic change that can be found in animals can be seen in rat pups. It has been found that when rat mothers give birth to their pups they will clean and groom them, which is a form of tactile stimulation. However it seems that not all mothers groom their young the same way, thus causing us to place them into two groups: High LG mothers and Low LG mothers. The high LG mothers groom and lick their young at a much more increased rate than the low LG mothers. As a result it was found that the pups of high LG mothers were healthier, grew at a good rate, and were all around much better off than the pups raised by low LG mothers. Therefore it seems that the way rat pups develop is not exactly genetic, but epigenetic. Further research discovered that the licking of the mother triggers the hippocampus in the rat pup, which then stimulatea the hypothalamus which releases CRF that stimulates the pituitary to release ACTH which finally causes the adrenal to release glucocoritchoids. This cascade of events all caused by the licking and grooming of the mother causes that pup to have decreased CRF expression in the hypothalamus, reduced ACTH and glucocortichoid responses to acute stress, and significantly increased glucocortichoid receptor expression.
Etymology and definitions
Epigenetics (as in "epigenetic landscapeEpigenetic landscape
Epigenetic landscape is a metaphor for biological development. Its originator, Conrad Hal Waddington, said that cell fates were established in development much like a marble rolls down to the point of lowest local elevation...
") was coined by C. H. Waddington
Conrad Hal Waddington
Conrad Hal Waddington CBE FRS FRSE was a developmental biologist, paleontologist, geneticist, embryologist and philosopher who laid the foundations for systems biology...
in 1942 as a portmanteau of the words genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
and epigenesis
Epigenesis (biology)
In biology, epigenesis has at least two distinct meanings:* the unfolding development in an organism, and in particular the development of a plant or animal from an egg or spore through a sequence of steps in which cells differentiate and organs form;...
. Epigenesis is an old word which has more recently been used (see preformationism
Preformationism
In the history of biology, preformationism is either the specific contention that all organisms were created at the same time, and that succeeding generations grow from homunculi, animalcules, or other fully formed but miniature versions of themselves that have existed since the beginning of...
for historical background) to describe the differentiation of cells from their initial totipotent state in embryonic development. 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
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
.
Robin Holliday
Robin Holliday
Robin Holliday PhD, FRS, FAA is a British molecular biologist. Heproposed a mechanism of DNA-strand exchange that attempted to explain gene-conversion events that occur during meiosis in fungi. That model first proposed in 1964 and is now known as the Holliday Junction.-Education and...
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 modern usage of the word in scientific discourse 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 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 similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
", and refers to the overall epigenetic state of a cell. The phrase "genetic code
Genetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....
" has also been adapted—the "epigenetic code
Epigenetic code
The epigenetic code is hypothesised 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...
" 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. 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
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
patterns.
The psychologist Erik Erikson
Erik Erikson
Erik Erikson was a Danish-German-American developmental psychologist and psychoanalyst known for his theory on social development of human beings. He may be most famous for coining the phrase identity crisis. His son, Kai T...
used the term epigenetic in his theory of psychosocial development. That usage, however, is of primarily historical interest.
Molecular basis of epigenetics
The molecular basis of epigenetics is complex. It involves modifications of the activation of certain genes, but not the basic structure of DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. Additionally, the chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
proteins associated with DNA may be activated or silenced. This accounts for why the differentiated cells in a multi-cellular organism express only the genes that are necessary for their own activity. Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic changes are inherited from one generation to the next. This raises the question of whether or not epigenetic changes in an organism can alter the basic structure of its DNA (see Evolution, below), a form of Lamarckism
Lamarckism
Lamarckism is the idea that an organism can pass on characteristics that it acquired during its lifetime to its offspring . It is named after the French biologist Jean-Baptiste Lamarck , who incorporated the action of soft inheritance into his evolutionary theories...
.
Specific epigenetic processes include paramutation
Paramutation
In epigenetics, paramutation is an interaction between two alleles of a single locus, resulting in a heritable change of one allele that is induced by the other allele...
, bookmarking
Bookmarking
In genetics and epigenetics, bookmarking is a biological phenomenon believed to function as an epigenetic mechanism for transmitting cellular memory of the pattern of gene expression in a cell, throughout mitosis, to its daughter cells...
, imprinting
Imprinting (genetics)
Genomic imprinting is a genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. It is an inheritance process independent of the classical Mendelian inheritance. Imprinted alleles are silenced such that the genes are either expressed only from the non-imprinted...
, gene silencing
Gene silencing
Gene silencing is a general term describing epigenetic processes of gene regulation. The term gene silencing is generally used to describe the "switching off" of a gene by a mechanism other than genetic modification...
, X chromosome inactivation
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
, position effect
Position effect
Position effect is the effect on the expression of a gene when its location in a chromosome is changed, often by translocation. This has been well described in Drosophila with respect to eye color and is known as position effect variegation ....
, reprogramming
Reprogramming
Reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development. After fertilization some cells of the newly formed embryo migrate to the germinal ridge and will eventually become the germ cells...
, transvection
Transvection (genetics)
Transvection is an epigenetic phenomenon that results from an interaction between an allele on one chromosome and the corresponding allele on the homologous chromosome. Transvection can lead to either gene activation or repression...
, maternal effect
Maternal effect
A maternal effect is a situation where the phenotype of an organism is determined not only by the environment it experiences and its genotype, but also by the environment and phenotype of its mother...
s, the progress of carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
, many effects of teratogens, regulation of histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
modifications and heterochromatin
Heterochromatin
Heterochromatin is a tightly packed form of DNA, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin...
, and technical limitations affecting parthenogenesis
Parthenogenesis
Parthenogenesis is a form of asexual reproduction found in females, where growth and development of embryos occur without fertilization by a male...
and cloning
Cloning
Cloning in biology is the process of producing similar populations of genetically identical individuals that occurs in nature when organisms such as bacteria, insects or plants reproduce asexually. Cloning in biotechnology refers to processes used to create copies of DNA fragments , cells , or...
.
Epigenetic research uses a wide range of molecular biologic techniques to further our understanding of epigenetic phenomena, including chromatin immunoprecipitation
Chromatin immunoprecipitation
Chromatin Immunoprecipitation is a type of immunoprecipitation experimental technique used to investigate the interaction between proteins and DNA in the cell. It aims to determine whether specific proteins are associated with specific genomic regions, such as transcription factors on promoters or...
(together with its large-scale variants ChIP-on-chip
ChIP-on-chip
ChIP-on-chip is a technique that combines chromatin immunoprecipitation with microarray technology . Like regular ChIP, ChIP-on-chip is used to investigate interactions between proteins and DNA in vivo...
and ChIP-Seq), fluorescent in situ hybridization
Fluorescent in situ hybridization
FISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification (DamID
DamID
DamID is a molecular biology protocol used to map the binding sites of DNA- and chromatin-binding proteins in eukaryotes. DamID identifies binding sites by expressing the proposed DNA-binding protein as a fusion protein with DNA methyltransferase...
) and bisulfite sequencing
Bisulfite sequencing
Bisulfite sequencing is the use of bisulfite treatment of DNA to determine its pattern of methylation. DNA methylation was the first discovered epigenetic mark, and remains the most studied...
. Furthermore, the use of bioinformatic methods is playing an increasing role (computational epigenetics
Computational epigenetics
Computational epigeneticsuses bioinformatic methods to complement experimental research in epigenetics. Due to the recent explosion of epigenome datasets, computational methods play an increasing role in all areas of epigenetic research.-Definition:...
).
Mechanisms
Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:DNA methylation and chromatin remodeling
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
of a cell or individual is affected by which of its genes are transcribed, heritable transcription states
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
can give rise to epigenetic effects. There are several layers of regulation of gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
. One way that genes are regulated is through the remodeling of chromatin. Chromatin is the complex of DNA and the histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
proteins with which it associates. Histone proteins are little spheres that DNA wraps around. If the way that DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:
- The first way is post translational modification of the amino acids that make up histone proteins. Histone proteins are made up of long chains of amino acids. If the amino acids that are in the chain are changed, the shape of the histone sphere might be modified. DNA is not completely unwound during replication. It is possible, then, that the modified histones may be carried into each new copy of the DNA. Once there, these histones may act as templates, initiating the surrounding new histones to be shaped in the new manner. By altering the shape of the histones around it, these modified histones would ensure that a differentiated cell would stay differentiated, and not convert back into being a stem cell.
- The second way is the addition of methyl groups to the DNA, mostly at CpG siteCpG siteCpG sites or CG sites are regions of DNA where a cytosine nucleotide occurs next to a guanine nucleotide in the linear sequence of bases along its length. "CpG" is shorthand for "—C—phosphate—G—", that is, cytosine and guanine separated by only one phosphate; phosphate links any two nucleosides...
s, to convert cytosineCytosineCytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
to 5-methylcytosine5-Methylcytosine5-Methylcytosine is a methylated form of the DNA base cytosine that may be involved in the regulation of gene transcription. When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered .In the figure on the right, a methyl group, is...
. 5-Methylcytosine performs much like a regular cytosine, pairing up with a guanine. However, some areas of the genome are methylated more heavily than others, and highly methylated areas tend to be less transcriptionally active, through a mechanism not fully understood. Methylation of cytosines can also persist from the germ line of one of the parents into the zygote, marking the chromosome as being inherited from this parent (genetic imprinting).
The way that the cells stay differentiated in the case of DNA methylation is clearer to us than it is in the case of histone shape. Basically, certain enzymes (such as DNMT1
DNA methyltransferase
In biochemistry, the DNA methyltransferase family of enzymescatalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions...
) have a higher affinity for the methylated cytosine. If this enzyme reaches a "hemimethylated" portion of DNA (where methylcytosine is in only one of the two DNA strands) the enzyme will methylate the other half.
Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
, methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
, ubiquitylation, phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and sumoylation. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
s 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 it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, thus loosening the DNA from the histone. When this occurs, complexes like SWI/SNF
SWI/SNF
SWI/SNF is a yeast nucleosome remodeling complex composed of several proteins – products of the SWI and SNF genes as well as several other polypeptides...
and other transcriptional factors can bind to the DNA and allow transcription to occur. This is the "cis" model of epigenetic function. In other words, changes to the histone tails have a direct affect on the DNA itself.
Another model of epigenetic function is the "trans" model. In this model changes to the histone tails act indirectly on the DNA. For example, lysine acetylation may create a binding site for chromatin modifying enzymes (and basal transcription machinery as well). This Chromatin Remodeler can then cause changes to the state of the chromatin. 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
SWI/SNF
SWI/SNF is a yeast nucleosome remodeling complex composed of several proteins – products of the SWI and SNF genes as well as several other polypeptides...
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 heterochromatin
Heterochromatin
Heterochromatin is a tightly packed form of DNA, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin...
). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein HP1
Heterochromatin protein 1
The family of Heterochromatin Protein 1 are highly conserved adapter proteins, which have important functions in the cell nucleus...
recruits HP1 to K9 methylated regions. One example that seems to refute this 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 has been shown that the histone lysine methyltransferase (KMT) is responsible for this methylation activity in the pattern of histones H3 & H4. This enzyme utilizes a catalytically active site called the SET domain (Suppressor of variegation, Enhancer of zeste, Trithorax). The SET domain is a 130-amino acid sequence involved in modulating gene activities. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone.
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
Histone code
The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code...
.
DNA methylation frequently occurs in repeated sequences, and helps to suppress the expression and mobility of 'transposable elements': Because 5-methylcytosine
5-Methylcytosine
5-Methylcytosine is a methylated form of the DNA base cytosine that may be involved in the regulation of gene transcription. When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered .In the figure on the right, a methyl group, is...
is chemically very similar to thymidine
Thymidine
Thymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...
, 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
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferase
DNA methyltransferase
In biochemistry, the DNA methyltransferase family of enzymescatalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions...
s, 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 DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
, and therefore is often referred to as the ‘maintenance' methyltransferase. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.
Histones H3 and H4 can also be manipulated through demethylation using histone lysine demethylase (KDM). This recently identified enzyme has a catalytically active site called the Jumonji domain (JmjC). The demethylation occurs when JmjC utilizes multiple cofactors to hydroxylate the methyl group, thereby removing it. JmjC is capable of demethylating mono-, di-, and tri-methylated substrates. .
Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of states of larger chromosomal regions are often thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. A simplified stochastic model for this type of epigenetics is found
here
.
Because DNA methylation and chromatin remodeling 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 remodeling is not always inherited, and not all epigenetic inheritance involves chromatin remodeling.
It has been suggested that the histone code
Histone code
The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code...
could be mediated by the effect of small RNAs. The recent discovery and characterization of a vast array of small (21- to 26-nt), non-coding RNAs suggests that there is an RNA component, possibly involved in epigenetic gene regulation. Small interfering RNA
Small interfering RNA
Small interfering RNA , sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA molecules, 20-25 nucleotides in length, that play a variety of roles in biology. The most notable role of siRNA is its involvement in the RNA interference pathway, where it...
s can modulate transcriptional gene expression via epigenetic modulation of targeted promoters.
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, Hnf4Hnf4
HNF4 is a nuclear receptor protein mostly expressed in the liver, gut, kidney, and pancreatic beta cells that is critical for liver development...
and MyoD
MyoD
MyoD is a protein with a key role in regulating muscle differentiation. MyoD belongs to a family of proteins known as myogenic regulatory factors . These bHLH transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 .MyoD is one...
enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
activity of the proteins they encode. RNA signalling includes differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. Other epigenetic changes are mediated by the production of different splice forms
Splicing (genetics)
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
of RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
, or by formation of double-stranded RNA (RNAi
RNAI
RNAI is a non-coding RNA that is an antisense repressor of the replication of some E. coli plasmids, including ColE1. Plasmid replication is usually initiated by RNAII, which acts as a primer by binding to its template DNA. The complementary RNAI binds RNAII prohibiting it from its initiation role...
). 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
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion
Diffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
. A large amount of RNA and protein is contributed to the zygote
Zygote
A zygote , or zygocyte, is the initial cell formed when two gamete cells are joined by means of sexual reproduction. In multicellular organisms, it is the earliest developmental stage of the embryo...
by the mother during oogenesis
Oogenesis
Oogenesis, ovogenesis or oögenesis is the creation of an ovum . It is the female form of gametogenesis. The male equivalent is spermatogenesis...
or via nurse cell
Nurse cell
-Human physiology:Nurse cells are specialized macrophages residing in the bone marrow that assist in the development of red blood cells. They absorb the nuclei of immature red blood cells and may provide growth factors to help the red blood cells mature...
s, resulting in maternal effect
Maternal effect
A maternal effect is a situation where the phenotype of an organism is determined not only by the environment it experiences and its genotype, but also by the environment and phenotype of its mother...
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
PrionPrion
A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...
s are infectious forms of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s. 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 infectious disease
Transmissible spongiform encephalopathy
Transmissible spongiform encephalopathies , also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an...
, 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.
Fungal prions are considered epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
in 1965 and 1971, are the two best 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 nonsense mutation
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
s 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
In ciliateCiliate
The ciliates are a group of protozoans characterized by the presence of hair-like organelles called cilia, which are identical in structure to flagella but typically shorter and present in much larger numbers with a different undulating pattern than flagella...
s such as Tetrahymena
Tetrahymena
Tetrahymena are free-living ciliate protozoa that can also switch from commensalistic to pathogenic modes of survival. They are common in fresh-water. Tetrahymena species used as model organisms in biomedical research are T. thermophila and T. pyriformis.- T...
and Paramecium
Paramecium
Paramecium is a group of unicellular ciliate protozoa, which are commonly studied as a representative of the ciliate group, and range from about 0.05 to 0.35 mm in length. Simple cilia cover the body, which allow the cell to move with a synchronous motion at speeds of approximately 12 body...
, 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.
Development
Somatic epigenetic inheritance, 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, morphogenMorphogen
A morphogen is a substance governing the pattern of tissue development, and the positions of the various specialized cell types within a tissue...
s 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 mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s, 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 remodeling
Chromatin remodeling
Chromatin remodeling is the enzyme-assisted movement of nucleosomes on DNA.This is performed by chromatin remodeling complexes like SWI/SNF , RSC and Imitation SWI complexes ....
, 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 as it tends to be multidimensional in nature. Congenital genetic disease is well understood, and it is also clear that epigenetics can play a role, for example, in the case of Angelman syndromeAngelman syndrome
Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor....
and Prader-Willi syndrome
Prader-Willi syndrome
Prader–Willi syndrome is a rare genetic disorder in which seven genes on chromosome 15 are deleted or unexpressed on the paternal chromosome...
. These are normal genetic diseases caused by gene deletions or inactivation of the genes, 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.
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 paramutationParamutation
In epigenetics, paramutation is an interaction between two alleles of a single locus, resulting in a heritable change of one allele that is induced by the other allele...
observed in maize
Maize
Maize known in many English-speaking countries as corn or mielie/mealie, is a grain domesticated by indigenous peoples in Mesoamerica in prehistoric times. The leafy stalk produces ears which contain seeds called kernels. Though technically a grain, maize kernels are used in cooking as a vegetable...
). 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
Weismann barrier
The Weismann barrier is the principle that hereditary information moves only from genes to body cells, and never in reverse. In more precise terminology hereditary information moves only from germline cells to somatic cells .This does not refer to the central dogma of molecular biology which...
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
Modern evolutionary synthesis
The modern evolutionary synthesis is a union of ideas from several biological specialties which provides a widely accepted account of evolution...
.
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. Interestingly, recent analysis have suggested that members of the APOBEC/AID family of cytosine deaminases are capable of simultaneously mediating genetic and epigenetic inheritance using similar molecular mechanisms.
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 meaning 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
Agouti gene
The Agouti gene is responsible for determining whether a mammal's coat is banded or of a solid color . The chief product of the Agouti gene is Agouti signalling peptide , but there are a number of alternative splice products....
, which affects their fur color, weight, and propensity to develop cancer.
More than 100 cases of transgenerational epigenetic inheritance phenomena have been reported in a wide range of organisms, including prokaryotes, plants, and animals.
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 best-known case of imprinting in human disorders is that of Angelman syndromeAngelman syndrome
Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor....
and Prader-Willi syndrome
Prader-Willi syndrome
Prader–Willi syndrome is a rare genetic disorder in which seven genes on chromosome 15 are deleted or unexpressed on the paternal chromosome...
—both can be produced by the same genetic mutation, chromosome 15q partial deletion
Chromosome 15q partial deletion
Chromosome 15q partial deletion is an extremely rare human genetic disorder, caused by a chromosomal aberration in which the long arm of one copy of chromosome 15 is deleted, or partially deleted. If the mother's copy of the chromosomal arm is deleted, Angelman syndrome results. If the father's...
, 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 genomic imprinting in the region. Beckwith-Wiedemann syndrome
Beckwith-Wiedemann syndrome
Beckwith–Wiedemann syndrome is an overgrowth disorder usually present at birth characterized by an increased risk of childhood cancer and certain congenital features. Originally, Dr...
is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.
Transgenerational epigenetic observations
See main article Transgenerational epigeneticsTransgenerational epigenetics
Epigenetic inheritance is the transmittance of information from one generation to the next that affects the traits of offspring without alteration of the primary structure of DNA or from environmental cues...
Marcus Pembrey and colleagues also observed in the Överkalix study
Överkalix study
The Överkalix study was a study conducted on the physiological effects of various environmental factors on transgenerational epigenetic inheritance. The study was conducted utilizing historical records, including harvests and food prices, in Överkalix, a small isolated municipality in northeast...
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.
Cancer and developmental abnormalities
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 diethylstilbestrolDiethylstilbestrol
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers...
, arsenite
Arsenite
In chemistry an arsenite is a chemical compound containing an arsenic oxoanion where arsenic has oxidation state +3.The different forms of the anion are the next ones:* ortho-arsenite: AsO33-* meta-arsenite: AsO2-...
, hexachlorobenzene
Hexachlorobenzene
Hexachlorobenzene, or perchlorobenzene, is a chlorocarbon with the molecular formula C6Cl6. It is a fungicide formerly used as a seed treatment, especially on wheat to control the fungal disease bunt...
, and nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...
compounds.
Many teratogens exert specific effects on the fetus by epigenetic mechanisms. While epigenetic effects may preserve the effect of a teratogen such as diethylstilbestrol
Diethylstilbestrol
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers...
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. FDA label information for Vidaza(tm), a formulation of 5-azacitidine
5-Azacytidine
Azacitidine or 5-azacytidine, sold under the trade name Vidaza, is a chemical analogue of cytidine, a nucleoside present in DNA and RNA. Azacitidine and its deoxy derivative, decitabine , are used in the treatment of myelodysplastic syndrome...
(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.
Recent studies have shown that the Mixed Lineage Leukemia
MLL (gene)
Histone-lysine N-methyltransferase HRX is an enzyme that in humans is encoded by the MLL gene.MLL is a histone methyltransferase deemed a positive global regulator of gene transcription...
(MLL) gene causes leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control.
Other investigations have concluded that alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer. Gene expression in the prostate can be modulated by nutrition and lifestyle changes.
In 2008, the National Institutes of Health announced that $190 million had been earmarked for epigenetics research over the next five years. In announcing the funding, government officials noted that epigenetics has the potential to explain mechanisms of aging, human development, and the origins of cancer, heart disease, mental illness, as well as several other conditions. Some investigators, like Randy Jirtle, PhD, of Duke University Medical Center, think epigenetics may ultimately turn out to have a greater role in disease than genetics.
DNA methylation in cancer
DNA methylationDNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
is an important regulator of gene transcription and a large body of evidence has demonstrated that aberrant DNA methylation is associated with unscheduled gene silencing, and the genes with high levels of 5-methylcytosine in their promoter region are transcriptionally silent. DNA methylation is essential during embryonic development, and in somatic cells, patterns of DNA methylation are generally transmitted to daughter cells with a high fidelity. Aberrant DNA methylation patterns have been associated with a large number of human malignancies and found in two distinct forms: hypermethylation and hypomethylation compared to normal tissue. Hypermethylation is one of the major epigenetic modifications that repress transcription via promoter region of tumour suppressor genes. Hypermethylation typically occurs at CpG islands in the promoter region and is associated with gene inactivation. Global hypomethylation has also been implicated in the development and progression of cancer through different mechanisms.
Variant histones H2A in cancer
The histoneHistone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many nuclear processes by altering chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
structure. One of the key H2A variants, H2A.X, marks DNA damage, facilitating the recruitment of DNA repair proteins to restore genomic integrity. Another variant, H2A.Z, plays an important role in both gene activation and repression. A high level of H2A.Z expression is ubiquitously detected in many cancers and is significantly associated with cellular proliferation and genomic instability.
Cancer treatment
Current research has shown that epigenetic pharmaceuticals could be a putative replacement or adjuvant therapy for currently accepted treatment methods such as radiationRadiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
and chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, or could enhance the effects of these current treatments. It has been shown that the epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones directly affects the formation and progression of cancer Epigenetics also has the factor of reversibility, a characteristic that other cancer treatments do not offer.
Drug development has mainly focused on Histone Acetyltransferase (HAT) and Histone Deacetylase (HDAC), including the introduction of the new pharmaceutical Vorinostat
Vorinostat
Vorinostat or suberoylanilide hydroxamic acid is a member of a larger class of compounds that inhibit histone deacetylases...
, a HDAC inhibitor, to the market. HDAC specifically has been shown to play an integral role in the progression of oral squamous cancer
Current front-runner candidates for new drug targets are Histone Lysine Methyltransferases
Histone methyltransferase
Histone methyltransferases are enzymes, histone-lysine N-methyltransferase and histone-arginine N-methyltransferase, that catalyze the transfer of one to three methyl groups from the cofactor S-Adenosyl methionine to lysine and arginine residues of histone proteins...
(KMT) and Protein Arginine Methyltransferases (PRMT).
Twin studies
Recent studies involving both dizygotic and monozygotic twins have produced some evidence of epigenetic influence in humans.Epigenetics in microorganisms
Bacteria make widespread use of postreplicative DNA methylation for the epigenetic control of DNA-protein interactions. Bacteria make use of DNA adenineAdenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
methylation (rather than DNA cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
methylation) as an epigenetic signal. DNA adenine methylation is important in bacteria virulence in organisms such as Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
, Salmonella
Salmonella
Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...
, Vibrio
Vibrio
Vibrio is a genus of Gram-negative bacteria possessing a curved rod shape, several species of which can cause foodborne infection, usually associated with eating undercooked seafood. Typically found in saltwater, Vibrio are facultative anaerobes that test positive for oxidase and do not form...
, Yersinia
Yersinia
Yersinia is a genus of bacteria in the family Enterobacteriaceae. Yersinia are Gram-negative rod shaped bacteria, a few micrometers long and fractions of a micrometer in diameter, and are facultative anaerobes. Some members of Yersinia are pathogenic in humans; in particular, Y. pestis is the...
, Haemophilus
Haemophilus
Not to be confused with Haemophilia.Haemophilus is a genus of Gram-negative, pleomorphic, coccobacilli bacteria belonging to the Pasteurellaceae family. While Haemophilus bacteria are typically small coccobacilli, they are categorized as pleomorphic bacteria because of the wide range of shapes they...
, and Brucella
Brucella
Brucella is a genus of Gram-negative bacteria. They are small , non-motile, non-encapsulated coccobacilli, which function as facultative intracellular parasites....
. In Alphaproteobacteria
Alphaproteobacteria
Alphaproteobacteria is a class of Proteobacteria. Like all Proteobacteria, they are Gram-negative.-Characteristics:The Alphaproteobacteria comprise most phototrophic genera, but also several genera metabolising C1-compounds , symbionts of plants and animals, and a group of pathogens, the...
, methylation of adenine regulates the cell cycle and couples gene transcription to DNA replication. In Gammaproteobacteria
Gammaproteobacteria
Gammaproteobacteria is a class of several medically, ecologically and scientifically important groups of bacteria, such as the Enterobacteriaceae , Vibrionaceae and Pseudomonadaceae. An exceeding number of important pathogens belongs to this class, e.g...
, adenine methylation provides signals for DNA replication, chromosome segregation, mismatch repair, packaging of bacteriophage, transposase activity and regulation of gene expression.
The filamentous fungus Neurospora crassa is a prominent model system for understanding the control and function of cytosine methylation. In this organisms, DNA methylation is associated with relics of a genome defense system called RIP (repeat-induced point mutation) and silences gene expression by inhibiting transcription elongation.
The yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
prion
Prion
A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...
PSI is generated by a conformational change of a translation termination factor, which is then inherited by daughter cells. This can provide a survival advantage under adverse conditions. This is an example of epigenetic regulation enabling unicellular organisms to respond rapidly to environmental stress. Prions can be viewed as epigenetic agents capable of inducing a phenotypic change without modification of the genome.
See also
- B chromosomeB chromosomeIn addition to the normal karyotype, wild populations of many animal, plant, and fungi species contain B chromosomes . By definition, these chromosomes are not essential for the life of a species, and are lacking in some of the individuals...
- Baldwin effectBaldwin effectThe Baldwin effect, also known as Baldwinian evolution or ontogenic evolution, is a theory of a possible evolutionary processes that was originally put forward in 1896 in a paper, "A New Factor in Evolution," by American psychologist James Mark Baldwin. The paper proposed a mechanism for specific...
- CentromereCentromereA centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment...
- Computational epigeneticsComputational epigeneticsComputational epigeneticsuses bioinformatic methods to complement experimental research in epigenetics. Due to the recent explosion of epigenome datasets, computational methods play an increasing role in all areas of epigenetic research.-Definition:...
- DNA demethylationDNA demethylationDNA demethylation is a process of removal of methyl group from nucleotide in DNA. DNA demethylation could be passive and active. Passive process takes place in the absence of methylation of newly synthesised DNA strands by DNMT1 during several replication rounds...
- Dutch famine of 1944 (scientific legacy)
- EmergenesisEmergenesisIn psychology, a trait is called emergenic if it is the result of a specific combination of several interacting genes . Emergenic traits will not run in families, but identical twins will share them...
- EpigenomicsEpigenomics-Epigenomics:Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome. The field is analogous to genomics and proteomics, which are the study of the genome and proteome of a cell...
- Epigenetic TheoryEpigenetic TheoryEpigenetic theory is an emergent theory of development that includes both the genetic origins of behavior and the direct influence that environmental forces have, over time, on the expression of those genes...
- Evolutionary capacitanceEvolutionary capacitanceJust as electric capacitors store and release charge, by analogy evolutionary capacitance is the storage and release of variation. Living systems are robust to mutations. This means that living systems accumulate genetic variation without the variation having a phenotypic effect...
- Evolutionary developmental psychologyEvolutionary developmental psychologyEvolutionary developmental psychology, , is the application of the basic principles of Darwinian evolution, particularly natural selection, to explain contemporary human development...
- Histone codeHistone codeThe histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code...
- Human genomeHuman genomeThe human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
- Molecular biologyMolecular biologyMolecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
- NutriepigenomicsNutriepigenomicsNutriepigenomics is the study of food nutrients and their effects on human health through epigenetic modifications. There is now considerable evidence that nutritional imbalances during gestation and lactation are linked to non-communicable diseases, such as obesity, cardiovascular disease,...
- PreformationismPreformationismIn the history of biology, preformationism is either the specific contention that all organisms were created at the same time, and that succeeding generations grow from homunculi, animalcules, or other fully formed but miniature versions of themselves that have existed since the beginning of...
- Somatic epitypeSomatic epitypeA somatic epitype is a non-heritable epigenetic alteration in a gene. It is similar to conventional epigenetics in that it does not involve changes in the DNA primary sequence...
- Synthetic genetic arraySynthetic genetic arraySynthetic Genetic Array analysis is a high-throughput technique for exploring synthetic lethal and synthetic sick genetic interactions . SGA allows for the systematic construction of double mutants using a combination of recombinant genetic techniques, mating and selection steps...
- Weismann barrierWeismann barrierThe Weismann barrier is the principle that hereditary information moves only from genes to body cells, and never in reverse. In more precise terminology hereditary information moves only from germline cells to somatic cells .This does not refer to the central dogma of molecular biology which...
External links
- review (2009) to add to refs
- The Human Epigenome Project (HEP)
- The Epigenome Network of Excellence (NoE)
- The Epigenome Network of Excellence (NoE)- public international site
- DNA Is Not Destiny – Discover Magazine cover story
- BBC – Horizon – 2005 – The Ghost In Your Genes
- Epigenetics article at Hopkins Medicine
- Towards a global map of epigenetic variation