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Epigenetics

From Wikipedia, the free encyclopedia
For the unfolding of an organism or the theory that plants and animals develop in this way, see epigenesis (biology). For epigenetics in robotics, see developmental robotics.

In biology, and specifically geneticsepigenetics is the study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, hence the name epi- (Greek:επί- over, above) -genetics. These changes may remain through cell divisions 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;[1]instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.[2]

The best example of epigenetic changes in eukaryotic biology is the process of cellular differentiation. Duringmorphogenesistotipotent 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, blood vessels etc. as it continues to divide. It does so by activating some genes while inhibiting others.[3]

Contents

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[edit]Etymology and definitions

epigenetic mechanisms

Epigenetics (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the wordsgenetics and epigenesis.[4] Epigenesis is an old[5] 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."[6] Thusepigenetic 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.[7] 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 codeor DNA methylation patterns.

The psychologist Erik Erikson used the term epigenetic[when?] in his theory of psychosocial development. That usage, however, is of primarily historical interest.[8]

[edit]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 DNA. 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.[9] 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 paramutationbookmarkingimprintinggene silencingX chromosome inactivationposition effectreprogrammingtransvectionmaternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affectingparthenogenesis 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).

[edit]Mechanisms

Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:[10]

[edit]DNA methylation and chromatin remodeling

DNA associates with histone proteins to form chromatin.

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:

  1. 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.
  2. The second way is the addition of methyl groups to the DNA, mostly at CpG sites, to convert cytosine to 5-methylcytosine. 5-Methylcytosine performs much like a regular cytosine, pairing up with a guanine. However, some areas of 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) 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 acetylationmethylationubiquitylation,phosphorylation and sumoylation. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally correlated with transcriptional competence.

One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. 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 (Supressor 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.[11]

It should be emphasized that differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently than acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code.

DNA methylation frequently occurs in repeated sequences, and helps to suppress the expression and mobility of 'transposable elements':[12] Because 5-methylcytosine is chemically very similar to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation.DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A and DNMT3B, the loss of any of which is lethal in mice.[13] DNMT1 is the most abundant methyltransferase in somatic cells,[14] localizes to replication foci,[15] has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).[16] 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.[17]DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.[13][18]

Histones H3 and H4 can also be manipulated through demethylation using histone lysine demethylase (KDM). This recently identifited 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. .[19]

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.[20] 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 [21] .

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.[22]

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 RNAs can modulate transcriptional gene expression via epigenetic modulation of targeted promoters.[23]

[edit]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, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. 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.[24] 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 syncytiaor gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effectphenotypes. 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.[25]

[edit]Prions

For more details on this topic, see Prions.

Prions are infectious forms of proteins. 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.[26]

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.[27][28] 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 mutations in other genes.[29] 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.[30][31]

[edit]Structural inheritance systems

For more details on this topic, see Structural inheritance.

In ciliates such as Tetrahymena and Paramecium, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.[32]

[edit]Functions and consequences

[edit]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, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a "memory". In mammals, most cells terminally differentiate, with onlystem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin 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.[33]

[edit]Medicine

Epigenetics has many and varied potential medical applications. Congenital genetic disease is well understood, and it is also clear that epigenetics can play a role, for example, in the case of Angelman syndrome 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.[34]

[edit]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 paramutation observed in maize). Although most of these multigenerational epigenetic traits are gradually lost over several generations, the possibility remains that multigenerational epigenetics could be another aspect to evolution and adaptation. A sequestered germ line orWeismann 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.[35][36]

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.[37] 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.[37]Interestingly, recent analysis have suggested that members of the APOBEC family of cytosine deaminases are capable of simultaneously mediating genetic and epigenetic inheritance using similar molecular mechanisms.[38]

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.[39][40]

[edit]Transgenerational epigenetic observations

A comprehensive review of over 100 cases of transgenerational epigenetic inheritance reported the phenomena in a wide range of organisms including prokaryotes, plants, and animals. [41]

[edit]Epigenetic effects in humans

[edit]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.[42] The best-known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndrome—both can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.[43] 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.

[edit]Transgenerational epigenetic observations

Marcus Pembrey and colleagues also observed in the Överkalix study that the paternal (but not maternal) grandsons of Swedish boys 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.[44] The opposite effect was observed for females—the paternal (but not maternal) granddaughters of women who experienced famine while in the womb (and their eggs were being formed) lived shorter lives on average.[45]

[edit]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 diethylstilbestrolarsenitehexachlorobenzene, and nickelcompounds.

Many teratogens exert specific effects on the fetus by epigenetic mechanisms.[46][47] 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.[48] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.[49] 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.[50] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.[51]

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.[52]

Other investigations have concluded that alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer.[53]

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.[54]

[edit]Cancer Treatment

Current research has shown that epigenetic pharmaceuticals could be a putative replacement or adjuvant therapy for currently accepted treatment methods such as radiation and chemotherapy, or could enhance the effects of these current treatments.[55] 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[56] Epigenetics also has the factor of reversibility, a characteristic that other cancer treatments do not offer.[53]

Drug development has mainly focused on Histone Acetyltransferase (HAT) and Histone Deactylase (HDAC), including the introduction of the new pharmaceutical Vorinostat, a HDAC inhibitor, to the market.[57] HDAC specifically has been shown to play an integral role in the progression of oral squamous cancer [56]

Current front-runner candidates for new drug targets are Histone Lysine Methyltransferases (KMT) and Protein Arginine Methyltransferases (PRMT).[58]

[edit]Twin studies

Recent studies involving both dizygotic and monozygotic twins have produced some evidence of epigenetic influence in humans.[59][60][61]

[edit]Epigenetics in microorganisms

Bacteria make widespread use of postreplicative DNA methylation for the epigenetic control of DNA-protein interactions. Bacteria make use of DNA adenine methylation (rather than DNA cytosine methylation) as an epigenetic signal. DNA adenine methylation is important in bacteria virulence in organisms such as Escherichia coliSalmonella,VibrioYersiniaHaemophilus, 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.[62][63]

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.[64]

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.[63]

[edit]See also

[edit]Notes and references

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  2. ^ Special report: 'What genes remember' by Philip Hunter | Prospect Magazine May 2008 issue 146
  3. ^ Reik, Wolf (2007-05-23). "Stability and flexibility of epigenetic gene regulation in mammalian development"Nature 447 (May (online)): 425–432.doi:10.1038/nature05918PMID 17522676. Retrieved 2008-04-05.
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  5. ^ According to the Oxford English Dictionary:
    The word is used by W. Harvey,Exercitationes 1651, p. 148, and in theEnglish Anatomical Exercitations 1653, p. 272. It is explained to mean ‘partium super-exorientium additamentum’, ‘the additament of parts budding one out of another’.
    It is also worth quoting this adumbration of the definition given there (viz., "The formation of an organic germ as a new product"):
    theory of epigenesis: the theory that the germ is brought into existence (by successive accretions), and not merely developed, in the process of reproduction. [...] The opposite theory was formerly known as the ‘theory of evolution’; to avoid the ambiguity of this name, it is now spoken of chiefly as the ‘theory of preformation’, sometimes as that of ‘encasement’ or ‘emboîtement’.
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  8. ^ Epigenetics
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  17. ^ Robertson, KD; Wolffe AP (October 2000). "DNA methylation in health and disease"Nat Rev Genet 1(1): 11–19. doi:10.1038/35049533.PMID 11262868.
  18. ^ Li, E; Beard C and Jaenisch R (December 1993). "Role for DNA methylation in genomic imprinting".Nature 366 (6453): 362–365.doi:10.1038/366362a0PMID 8247133.
  19. ^ Nottke, A; Colaiácovo, MP; Shi, Y (2009). "Developmental role of the histone lysine demethylases". Development 6 (136): 879–89 pmid=19234061.
  20. ^ Rosenfeld, Jeffrey AWang, ZhibinSchones, Dustin;Zhao, KejiDeSalle, Rob; Zhang, Michael Q (31 March 2009). "Determination of enriched histone modifications in non-genic portions of the human genome."BMC Genomics 10 (143): 143.doi:10.1186/1471-2164-10-143PMID 19335899.
  21. ^ Dodd, I.B.; Micheelsen, M.A.; Sneppen, K.; Thon, G. (2007). "Theoretical Analysis of Epigenetic Cell Memory by Nucleosome Modification". Cell 129 (4): 813–822. doi:10.1016/j.cell.2007.02.053.PMID 17512413.
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  29. ^ S.W. Liebman and F. Sherman (1979)."Extrachromosomal psi+ determinant suppresses nonsense mutations in yeast"Journal of Bacteriology 139 (3): 1068–1071. PMID 225301.Free full text available
  30. ^ H.L. True and S.L. Lindquist (2000). "A yeast prion provides a mechanism for genetic variation and phenotypic diversity". Nature 407 (6803): 477–483.doi:10.1038/35035005PMID 11028992.
  31. ^ J. Shorter and S. Lindquist (2005). "Prions as adaptive conduits of memory and inheritance". Nature Reviews Genetics 6 (6): 435–450.doi:10.1038/nrg1616PMID 15931169.
  32. ^ Jan Sapp, Beyond the Gene. 1987 Oxford University Press. Jan Sapp, "Concepts of organization: the leverage of ciliate protozoa" . In S. Gilbert ed., Developmental Biology: A Comprehensive Synthesis, (New York: Plenum Press, 1991), 229-258. Jan Sapp, Genesis: The Evolution of Biology Oxford University Press, 2003. Cycles of Contingency: Developmental Systems and Evolution |last=Oyama |first=Susan |coauthors=Paul E. Griffiths, Russell D. Gray |year=2001 |publisher=MIT Press |isbn=0262650630 }}
  33. ^ Costa, Silvia; Shaw, Peter (2006). "'Open Minded' cells: how cells can change fate". Trends in Cell Biology 17 (3): 101–106.doi:10.1016/j.tcb.2006.12.005PMID 17194589.
  34. ^ Online 'Mendelian Inheritance in Man' (OMIM)105830
  35. ^ Jablonka, Eva; Marion J. Lamb (2005). Evolution in Four Dimensions. MIT Press. ISBN 0-262-10107-6.
  36. ^ See also Denis Noble The Music of Life see esp pp93-8 and p48 where he cites Jablonka & Lamb andMassimo Pigliucci's review of Jablonka and Lamb inNature 435, 565-566 (2 June 2005)
  37. a b O.J. Rando and K.J. Verstrepen (2007). "Timescales of Genetic and Epigenetic Inheritance".Cell 128 (4): 655–668.doi:10.1016/j.cell.2007.01.023PMID 17320504.
  38. ^ Chahwan R., Wontakal S.N., and Roa S. (2010). "Crosstalk between genetic and epigenetic information through cytosine deamination". Trends in Genetics 26(10): 443–448. doi:10.1016/j.tig.2010.07.005.PMID 20800313.
  39. ^ Cooney, CA, Dave, AA, and Wolff, GL (2002). "Maternal Methyl Supplements in Mice Affect Epigenetic Variation and DNA Methylation of Offspring". Journal of Nutrition 132 (8 Suppl): 2393S–2400S.PMID 12163699.available online
  40. ^ Waterland RA and Jirtle RL (August 2003)."Transposable elements: Targets for early nutritional effects on epigenetic gene regulation"Molecular and Cellular Biology 23 (15): 5293–5300.doi:10.1128/MCB.23.15.5293-5300.2003.PMID 12861015PMC 165709.
  41. ^ Jablonka, Eva; Gal Raz (June 2009)."Transgenerational Epigenetic Inheritance: Prevalence, Mechanisms, and Implications for the Study of Heredity and Evolution"The Quarterly Review of Biology 84(2): 131–176. doi:10.1086/598822.
  42. ^ A.J. Wood and A.J. Oakey (2006). "Genomic imprinting in mammals: Emerging themes and established theories"PLOS Genetics 2 (11): 1677–1685. doi:10.1371/journal.pgen.0020147.PMID 17121465. available online
  43. ^ J.H.M. Knoll, R.D. Nicholls, R.E. Magenis, J.M. Graham Jr, M. Lalande, S.A. Latt (1989). "Angelman and Prader-Willi syndromes share a common chromosome deletion but differ in parental origin of the deletion". American Journal of Medical Genetics 32 (2): 285–290. doi:10.1002/ajmg.1320320235.PMID 2564739.
  44. ^ Pembrey ME, Bygren LO, Kaati G, et al.. Sex-specific, male-line transgenerational responses in humans.Eur J Hum Genet 2006; 14: 159-66. PMID 16391557.Robert Winston refers to this study in a lecture; see also discussion at Leeds Universityhere
  45. ^http://www.pbs.org/wgbh/nova/transcripts/3413_genes.html
  46. ^ Bishop, JB; Witt KL and Sloane RA (December 1997). "Genetic toxiticities of human teratogens".Mutat Res 396 (1-2): 9–43.
  47. ^ Gurvich, N; Berman MG, Wittner BS et al. (July 2004)."Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo"FASEB J 19(9): 1166–1168. doi:10.1096/fj.04-3425fje.PMID 15901671.
  48. ^ Smithells, D (November 1998). "Does thalidomide cause second generation birth defects?". Drug Saf 19(5): 339–341. doi:10.2165/00002018-199819050-00001PMID 9825947.
  49. ^ Friedler, G (December 1996). "Paternal exposures: impact on reproductive and developmental outcome. An overview". Pharmacol Biochem Behav 55 (4): 691–700. doi:10.1016/S0091-3057(96)00286-9.PMID 8981601.
  50. ^ Cicero, TJ; Adams NL, Giodarno A et al. (March 1991). "Influence of morphine exposure during adolescence on the sexual maturation of male rats and the development of their offspring". J Pharmacol Exp Ther. 256 (3): 1086–1093. PMID 2005573.
  51. ^ Newbold, RR; Padilla-Banks E and Jefferson WN (June 2006). "Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations".Endocrinology 147 (6 Suppl): S11–S17.doi:10.1210/en.2005-1164PMID 16690809.
  52. ^ Mandall, SS (2010). "Mixed lineage leukemia: versatile player in epigenetics and human disease".The FEBS Journal 227 (8): 1789. doi:10.1111/j.1742-4658.2010.07605.xPMID 20236314.
  53. a b Li, LC; Carroll, PR; Dahiya, R (2005). "Epigenetic changes in prostate cancer: implication for diagnosis and treatment". Journal of the National Cancer Institute2 (97): 103–15. doi:10.1093/jnci/dji010.PMID 15657340.
  54. ^ Beil, Laura (Winter, 2008). "Medicine's New Epicenter? Epigenetics: New field of epigenetics may hold the secret to flipping cancer's "off" switch.". CURE (Cancer Updates, Research and Education).
  55. ^ Wang, LG; Chiao, JW (2010). "Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review)". International Journal of Oncology 3 (37): 533–9. PMID 20664922.
  56. a b Iglesias-Linares, A; Yañez-Vico, RM; González-Moles, MA (2010). "Potential role of HDAC inhibitors in cancer therapy: insights into oral squamous cell carcinoma". Oral Oncology 5 (46): 323–9.doi:10.1016/j.oraloncology.2010.01.009.PMID 20207580.
  57. ^ Spannhoff, A; Sippl, W; Jung, M (2009). "Cancer treatment of the future: Inhibitors of histone methyltransferases". The International Journal of Biochemistry & Cell Biology 1 (41): 4–11.doi:10.1016/j.biocel.2008.07.024.PMID 18773966.
  58. ^ "Toward the development of potent and selective bisubstrate inhibitors of protein arginine methyltransferases". Bioorganic & Medicinal Chemistry Letters 7 (20): 2103–5.doi:10.1016+pmid=20219369.
  59. ^ O'Connor, Anahad (2008-03-11). "The Claim: Identical Twins Have Identical DNA". New York Times. Retrieved 2010-05-02.
  60. ^ Kaminsky, Zachary A; Tang, T; Wang, SC; Ptak, C; Oh, GH; Wong, AH; Feldcamp, LA; Virtanen, C et al. (2009). "DNA methylation profiles in monozygotic and dizygotic twins". Nature Genetics 41 (2): 240–5.doi:10.1038/ng.286PMID 19151718.
  61. ^ Fraga, M. F.; Ballestar, E; Paz, MF; Ropero, S; Setien, F; Ballestar, ML; Heine-Suñer, D; Cigudosa, JC et al. (2005). "Epigenetic differences arise during the lifetime of monozygotic twins"Proceedings of the National Academy of Sciences 102 (30): 10604–9.doi:10.1073/pnas.0500398102PMID 16009939.PMC 1174919.
  62. ^ Casadesus J and Low D (September 2006)."Epigenetic Gene Regulation in the Bacterial World".Microbiol Mol Biol Rev 70 (3): 830–856.doi:10.1128/MMBR.00016-06PMID 16959970.
  63. a b Tost J (editor). (2008). Epigenetics. Caister Academic Press. ISBN 978-1-904455-23-3 .ISBN 1904455239.
  64. ^ Genome Res. 2009. 19: 427-437/doi: 10.1101/gr.086231.108

[edit]External links

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http://en.wikipedia.org/wiki/Epigenetics  16/8/9 - сохраню для иллюстрации правильного способа цитирования в конспектах. 14/1/11

Epigenetics

From Wikipedia, the free encyclopedia

For the unfolding of an organism or the theory that plants and animals develop in this way, see Epigenesis (biology).
For epigenetics in robotics, see Developmental robotics.
Image:Molbio-Header.svg

This article is part of the series on:

Gene expression
Molecular biology topic (portal)
(Glossary)

Introduction to Genetics
General flow: DNA > RNA > Protein
special transfers (RNA > RNA,
RNA > DNAProtein > Protein)
Genetic code
Transcription
Transcription (Transcription factors,
RNA Polymerase,promoter)

Prokaryotic / Eukaryotic

post-transcriptional modification
(hnRNA,Splicing)
Translation
Translation (Ribosome,tRNA)

Prokaryotic / Eukaryotic

post-translational modification
(functional groups, peptides,
structural changes
)
gene regulation
epigenetic regulation (Hox genes,
Genomic imprinting)
transcriptional regulation
post-transcriptional regulation
(sequestration,
alternative splicing,miRNA)
post-translational regulation
(reversible,irrevesible)

In biology, the term epigenetics refers to changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, hence the name epi- (Greek: over; above) -genetics. These changes may remain through cell divisionsfor 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;[1] instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.[2] The best example of epigenetic changes in eukaryotic biology is the process of cellular differentiation. Duringmorphogenesistotipotent stem cells become the various pluripotent cell lines of the embryowhich in turn become fully differentiated cells. In other words, a single fertilized egg cell - thezygote - changes into the many cell types including neurons, muscle cells, epithelium, blood vessels etc. as it continues to divide. It does so by activating some genes while inhibiting others.[3]

Contents

 [hide]

[edit]Etymology and definitions

According to Dr. Steve Folmar, the word epigenetics has had many definitions, and much of the confusion surrounding its usage relates to these definitions having changed over time. Initially it was used in a broader, less specific sense but it has become more narrowly linked to specific molecular phenomena occurring in organisms.[4]

Epigenetics (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the words genetics andepigenesis.[5] Epigenesis (see contrasting principle of preformationism) is an older word 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."[6] Thus epigenetic can be used to describe any aspect 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.[7] The Greek prefix epi- in epigeneticsimplies 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; 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.

Epigenetic was also used by the psychologist Erik Erikson in his Psychosocial development theory, however that usage is of primarily historical interest.[8] Other definition the epigenetics is heritable changes in gene expression that are, unlike mutations, not attributable to alterations in DNA sequence. Two predominant epigenetic mechanisms are DNA methylation and histone modification

[edit]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 ofDNA. 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 some epigenetic changes are inherited from one generation to the next.[9] Specific epigenetic processes include paramutationbookmarkingimprinting,gene silencingX chromosome inactivationposition effectreprogrammingtransvectionmaternal effects, the progress ofcarcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affectingparthenogenesis 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).

[edit]Mechanisms

Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:[10]

[edit]DNA methylation and chromatin remodeling

DNA associates with histone proteins to form chromatin.

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:

  1. 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.
  2. The second way is the addition of methyl groups to the DNA, mostly at CpG sites, to convert cytosine to 5-methylcytosine. 5-Methylcytosine performs much like a regular cytosine, pairing up with a G, so in the next round of cell division it will be replaced with a regular C. However, some areas of genome are methylated heavier than others and highly methylated areas tend to be transcriptionally less 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) 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 acetylationmethylationubiquitylationphosphorylation and sumoylation. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally correlated with transcriptional competence.

One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone and prevent them from repelling each other. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, causing the DNA to repel itself. When this occurs, complexes like SWI/SNFand other transcriptional factors can bind to the DNA, thus opening it up and exposing it to enzymes like RNA polymerase so transcription of the gene can occur.

In addition, the positively charged tails of histone proteins from one nucleosome may interact with the histone proteins on a neighboring nucleosome, causing them to pack closely. Lysine acetylation may interfere with these interactions, causing the chromatin structure to open up.

Lysine acetylation may also act as a beacon to recruit other activating chromatin modifying enzymes (and basal transcription machinery as well). Indeed, the bromodomain — a protein segment (domain) that specifically binds acetyl-lysine — is found in many enzymes that help activate transcription, including the SWI/SNF complex (on the protein polybromo). It may be that acetylation acts in this and the previous way to aid in transcriptional activation.

The idea that modifications act as docking modules for related factors is borne out 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 HP1recruits 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 should be emphasized that differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently than acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code.

DNA methylation frequently occurs in repeated sequences, and may help to suppress 'junk DNA':[11] Because 5-methylcytosine is chemically very similar to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A and DNMT3B, the loss of any of which is lethal in mice.[12] DNMT1 is the most abundant methyltransferase in somatic cells,[13] localizes to replication foci,[14] has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).[15] 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.[16] DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.[12][17]

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 [18] .

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.[19]

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 RNAs can modulate transcriptional gene expression via epigenetic modulation of targeted promoters.[20]

[edit]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, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. 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[21]. Other epigenetic changes are mediated by the production of different splice forms of RNA, or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are most often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effect phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.[22]

[edit]Prions

For more details on this topic, see Prions.

Prions are infectious forms of proteins. 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 ofinfectious 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.[23]

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.[24][25] 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 stopcodons, an effect which results in suppression of nonsense mutations in other genes.[26] 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.[27][28]

[edit]Structural inheritance systems

For more details on this topic, see Structural inheritance.

In ciliates such as Tetrahymena and Paramecium, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.[29]

[edit]Functions and consequences

[edit]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 in many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a "memory". In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin 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.[30]

[edit]Medicine

Epigenetics has many and varied potential medical applications. Congenital genetic disease is well understood, and it is also clear that epigenetics can play a role, for example, in the case of Angelman syndrome 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 essentiallyhemizygous 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.[31]

[edit]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 paramutation observed in maize). Although most of these multigenerational epigenetic traits are gradually lost over several generations, the possibility remains that multigenerational epigenetics could be another aspect to evolution and adaptation. These effects may require enhancements to the standard conceptual framework of the modern evolutionary synthesis.[32][33]

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.[34] 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.[34]

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.[35][36]

[edit]Transgenerational epigenetic observations

A comprehensive review of over 100 cases of transgenerational epigenetic inheritance reported the phenomina in a wide range of organisms including prokaryots, plants, and animals. [37]

[edit]Epigenetic effects in humans

[edit]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.[38] The most well-known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndrome—both can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.[39] 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.

[edit]Transgenerational epigenetic observations

Marcus Pembrey and colleagues also observed that the paternal (but not maternal) grandsons of Swedish boys who were exposed during preadolescence to famine in the 19th century were less likely to die of cardiovascular disease; if food was plentiful then diabetesmortality in the grandchildren increased, suggesting that this was a transgenerational epigenetic inheritance.[40] The opposite effect was observed for females -- the paternal (but not maternal) granddaughters of women who experienced famine while in the womb (and their eggs were being formed) lived shorter lives on average.[41]

[edit]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 diethylstilbestrolarsenitehexachlorobenzene, and nickel compounds.

Many teratogens exert specific effects on the fetus by epigenetic mechanisms.[42][43] 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.[44] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.[45] 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.[46] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.[47] 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.[48]

[edit]Twin studies

Recent studies involving both dizogotic and monozygotic twins have produced some evidence of epigenetic influence in humans.[49][50][51]

[edit]Epigenetics in microorganisms

Bacteria make widespread use of postreplicative DNA methylation for the epigenetic control of DNA-protein interactions. Bacteria make use of DNA adenine methylation (rather than DNA cytosine methylation) as an epigenetic signal. DNA adenine methylation is important in bacteria virulence in organisms such as Escherichia coliSalmonellaVibrioYersiniaHaemophilus, and Brucella. InAlphaproteobacteria, methylation of adenine regulates the cell cycle and couples gene transcription to DNA replication. InGammaproteobacteria, adenine methylation provides signals for DNA replication, chromosome segregation, mismatch repair, packaging of bacteriophage, transposase activity and regulation of gene expression.[52][53]

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.[53]

[edit]See also


[edit]Epigenetics Journals and Online Media

Key advances and emerging trends in the field of epigenetics are documented in most scientific journals routinely. Two journals,Epigenetics[1] (Landes Bioscience) and the Open Source, Epigenetics and Chromatin [2] (BioMed Central) are dedicated to the field. EpiGenie [3], an online media site, provides coverage of epigenetics research highlights from all scientific journals.

[edit]Further reading

  • Oskar Hertwig, 1849-1922. Biological problem of today: preformation or epigenesis? The basis of a theory of organic development. W. Heinemann: London, 1896.
  • Rudolf Jaenisch and A. Bird (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33 (Suppl) 245-254.
  • Joshua Lederberg,The Meaning of Epigenetics, The Scientist 15(18):6, Sep. 17, 2001.
  • R. J. Sims III, K. Nishioka and D. Reinberg (2003) Histone lysine methylation: a signature for chromatin function. Trends Genet. 19, 629-637.
  • Rupert Sheldrake, A New Biology, morphogenetic fields.
  • B. D. Strahl and C. D. Allis (2000) The language of covalent histone modifications. Nature 403, 41-45.
  • C.H. Waddington (1942), The epigenotypeEndeavour 1, 18–20.
  • B. McClintock (1978) Mechanisms that Rapidly Reorganize the Genome. Stadler Symposium vol 10:25-48
  • G.W. Grimes; K.J. Aufderheide; Cellular Aspects of Pattern Formation: the Problem of Assembly. Monographs in Developmental Biology, Vol. 22. Karger, Basel (1991)
  • Eva Jablonka and Marion J. Lamb Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life The MIT Press (2005) ISBN 978-0262101073
  • Article on The Philosophy of Molecular and Developmental Biology to appear in Blackwell’s Guide to Philosophy of Science,. P.K. Machamer and M. Silberstein (Eds).
  • Epigenetics edited by C. David Allis, Thomas Jenuwein, Danny Reinberg, and Marie-Laure Caparros. Cold Spring Harbor Press, 2007.
  • Evolution by Nicholas Barton, Derek Briggs, Jonathan Eisen, David Goldstein, and Nipam Patel. Cold Spring Harbor Press, 2007.
  • Chromatin and Gene Regulation: Mechanisms in Epigenetics by Bryan Turner. Blackwell Publishing, 2002.
  • Epigenetics edited by J. Tost. Caister Academic Press, 2008.
  • RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity edited by K. V. Morris. Caister Academic Press, 2008.
  • Epigenetic biomarkers in psychiatric disorders British Journal of Pharmacology (2008) 155, 795–796; doi:10.1038/bjp.2008.254; published online 23 June 2008

[edit]Notes and references

  1. ^ Adrian Bird (2007). "Perceptions of epigenetics". Nature 447: 396–398. doi:10.1038/nature05913. PMID 17522671
  2. ^ Special report: 'What genes remember' by Philip Hunter | Prospect Magazine May 2008 issue 146
  3. ^ Reik, Wolf (2007-05-23). "Stability and flexibility of epigenetic gene regulation in mammalian development". Nature 447 (May (online)): 425–432.doi:10.1038/nature05918. Retrieved on 2008-04-05.
  4. ^ Roloff, T.C., Nuber, U.A., 2005 Chromatin , epigenetics and stem cells. Eur J Cell Biol. 84, 123-135
  5. ^ C.H. Waddington (1942) (1977). "The epigenotype". Endeavour 1: 18–20. doi:10.1016/0160-9327(77)90005-9.
  6. ^ Holliday, R., 1990. Mechanisms for the control of gene activity during development. Biol. Rev. Cambr. Philos. Soc. 65, 431-471
  7. ^ Russo, V.E.A., Martienssen, R.A., Riggs, A.D., 1996 Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Plainview, NY.
  8. ^ Epigenetics
  9. ^ V.L. Chandler (2007). "Paramutation: From Maize to Mice". Cell 128: 641–645. doi:10.1016/j.cell.2007.02.007.
  10. ^ Jablonka, E; Lamb MJ and Lachmann M (September 1992). "Evidence, mechanisms and models for the inheritance of acquired characteristics". J. Theoret. Biol. 158 (2): 245–268. doi:10.1016/S0022-5193(05)80722-2.
  11. ^ Chédin, F (1992). "The Chedin Laboratory". Retrieved on 2006-12-28.
  12. a b Li, E; Bestor TH and Jaenisch R (June 1992). "Targeted mutation of the DNA methyltransferase gene results in embryonic lethality". Cell 69 (6): 915–926. doi:10.1016/0092-8674(92)90611-F.
  13. ^ Robertson, KD; Uzyolgi E, Lian G et al. (June 1999). "The human DNA methyltransferases (DNMTs) 1, 3a, 3b: Coordinate mRNA expression in normal tissues and overexpression in tumors". Nucleic Acids Res 27 (11): 2291–2298. doi:10.1093/nar/27.11.2291PMID 10325416.
  14. ^ Leonhardt, H; Page AW, Weier HU, Bestor TH (November 1992). "A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei". Cell 71 (5): 865–873. doi:10.1016/0092-8674(92)90561-P.
  15. ^ Chuang, LS; Ian HI, Koh TW et al. (September 1997). "Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1". Science277 (5334): 1996–2000. doi:10.1126/science.277.5334.1996PMID 9302295.
  16. ^ Robertson, KD; Wolffe AP (October 2000). "DNA methylation in health and disease". Nat Rev Genet 1 (1): 11–19. doi:10.1038/35049533.
  17. ^ Li, E; Beard C and Jaenisch R (December 1993). "Role for DNA methylation in genomic imprinting". Nature 366 (6453): 362–365.doi:10.1038/366362a0.
  18. ^ I.B. Dodd, M.A. Micheelsen, K. Sneppen and G. Thon (2007). Theoretical Analysis of Epigenetic Cell Memory by Nucleosome Modification Cell 129:813-822.
  19. ^ Mark Ptashne, 2007. On the use of the word ‘epigenetic’. Current Biology17(7):R233-R236. doi:10.1016/j.cub.2007.02.030
  20. ^ Morris KV (2008). "Epigenetic Regulation of Gene Expression". RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press. ISBN 978-1-904455-25-7.
  21. ^ Mattick JS, Amaral PP, Dinger ME, Mercer TR, Mehler MF. RNA regulation of epigenetic processes. Bioessays. 2009 Jan;31(1):51-9. Review. PMID: 19154003
  22. ^ Choi CQ (2006-05-25). "The Scientist: RNA can be hereditary molecule". The Scientist. Retrieved on 2006.
  23. ^ A. Yool and W.J. Edmunds (1998). "Epigenetic inheritance and prions". Journal of Evolutionary Biology 11: 241–242. doi:10.1007/s000360050085.
  24. ^ B.S. Cox (1965). "[PSI], a cytoplasmic suppressor of super-suppression in yeast". Heredity 20: 505–521. doi:10.1038/hdy.1965.65.
  25. ^ F. Lacroute (1971). "Non-Mendelian mutation allowing ureidosuccinic acid uptake in yeast". Journal of Bacteriology 106: 519–522.
  26. ^ S.W. Liebman and F. Sherman (1979). "Extrachromosomal psi+ determinant suppresses nonsense mutations in yeast". Journal of Bacteriology 139 (3): 1068–1071. Free full text available
  27. ^ H.L. True and S.L. Lindquist (2000). "A yeast prion provides a mechanism for genetic variation and phenotypic diversity". Nature 407: 477–483.doi:10.1038/35035005.
  28. ^ J. Shorter and S. Lindquist (2005). "Prions as adaptive conduits of memory and inheritance". Nature Reviews Genetics 6 (6): 435–450.doi:10.1038/nrg1616.
  29. ^ Oyama, Susan; Paul E. Griffiths, Russell D. Gray (2001). Cycles of Contingency: Developmental Systems and Evolution. MIT Press. ISBN 0262650630.
  30. ^ Silvia Costa and Peter Shaw. 2006. 'Open Minded' cells: how cells can change fate. Trends in Cell Biology 17(3):101-106.doi:10.1016/j.tcb.2006.12.005
  31. ^ Online 'Mendelian Inheritance in Man' (OMIM) 105830
  32. ^ Jablonka, Eva; Marion J. Lamb (2005). Evolution in Four Dimensions. MIT Press. ISBN 0-262-10107-6.
  33. ^ See also Denis Noble The Music of Life see esp pp93-8 and p48 where he cites Jablonka & Lamb and Massimo Pigliucci's review of Jablonka and Lamb in Nature 435, 565-566 (2 June 2005)
  34. a b O.J. Rando and K.J. Verstrepen (2007). "Timescales of Genetic and Epigenetic Inheritance". Cell 128: 655–668. doi:10.1016/j.cell.2007.01.023.
  35. ^ Cooney, CA, Dave, AA, and Wolff, GL (2002). "Maternal Methyl Supplements in Mice Affect Epigenetic Variation and DNA Methylation of Offspring".Journal of Nutrition 132: 2393S–2400S.available online
  36. ^ Waterland RA and Jirtle RL (August 2003). "Transposable elements: Targets for early nutritional effects on epigenetic gene regulation". Molecular and Cellular Biology 23 (15): 5293–5300. doi:10.1128/MCB.23.15.5293-5300.2003PMID 12861015.
  37. ^ Jablonka, Eva; Gal Raz (June 2009). "Transgenerational Epigenetic Inheritance: Prevalence, Mechanisms, and Implications for the Study of Heredity and Evolution". The Quarterly Review of Biology 84 (2): 131–176. doi:10.1086/598822.
  38. ^ A.J. Wood and A.J. Oakey (2006). "Genomic imprinting in mammals: Emerging themes and established theories". PLOS Genetics 2 (11): 1677–1685.doi:10.1371/journal.pgen.0020147. available online
  39. ^ J.H.M. Knoll, R.D. Nicholls, R.E. Magenis, J.M. Graham Jr, M. Lalande, S.A. Latt (1989). "Angelman and Prader-Willi syndromes share a common chromosome deletion but differ in parental origin of the deletion". American Journal of Medical Genetics 32: 285–290. doi:10.1002/ajmg.1320320235.
  40. ^ Pembrey ME, Bygren LO, Kaati G, et al.. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006; 14: 159-66. PMID 16391557Robert Winston refers to this study in a lecture; see also discussion at Leeds Universityhere
  41. ^ http://www.pbs.org/wgbh/nova/transcripts/3413_genes.html
  42. ^ Bishop, JB; Witt KL and Sloane RA (December 1997). "Genetic toxiticities of human teratogens". Mutat Res 396 (1-2): 9–43.
  43. ^ Gurvich, N; Berman MG, Wittner BS et al. (July 2004). "Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo".Faseb J 19 (9): 1166–1168. doi:10.1096/fj.04-3425fjePMID 15901671.
  44. ^ Smithells, D (November 1998). "Does thalidomide cause second generation birth defects?". Drug Saf 19 (5): 339–341. doi:10.2165/00002018-199819050-00001.
  45. ^ Friedler, G (December 1996). "Paternal exposures: impact on reproductive and developmental outcome. An overview". Pharmacol Biochem Behav 55(4): 691–700. doi:10.1016/S0091-3057(96)00286-9.
  46. ^ Cicero, TJ; Adams NL, Giodarno A et al. (March 1991). "Influence of morphine exposure during adolescence on the sexual maturation of male rats and the development of their offspring". J Pharmacol Exp Ther. 256 (3): 1086–1093.
  47. ^ Newbold, RR; Padilla-Banks E and Jefferson WN (June 2006). "Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations". Endocrinology 147 (6 Suppl): S11–S17. doi:10.1210/en.2005-1164PMID 16690809.
  48. ^ Beil, Laura (Winter, 2008). "Medicine's New Epicenter? Epigenetics: New field of epigenetics may hold the secret to flipping cancer's "off" switch.". CURE (Cancer Updates, Research and Education).
  49. ^ "The Claim: Identical Twins Have Identical DNA". New York Times. 2008.
  50. ^ Kaminsky, Zachary A (2009). "DNA methylation profiles in monozygotic and dizygotic twins". Nature Genetics 41: 240. doi:10.1038/ng.286.
  51. ^ Fraga, M. F. (2005). "Epigenetic differences arise during the lifetime of monozygotic twins". Proceedings of the National Academy of Sciences 102: 10604. doi:10.1073/pnas.0500398102.
  52. ^ Casadesus J and Low D (September 2006). "Epigenetic Gene Regulation in the Bacterial World". Microbiol Mol Biol Rev 70 (3): 830–856.doi:10.1128/MMBR.00016-06.
  53. a b Tost J (editor). (2008). Epigenetics. Caister Academic Press. ISBN 978-1-904455-23-3 .

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