Epigenetics 49033 224229459 2008-07-07T22:13:58Z 90.213.126.184 {{technical}} {{MolBioGeneExp}}{{For|the unfolding of an organism or the theory that plants and animals develop in this way| Epigenesis (biology)}} In [[biology]], the term '''epigenetics''' refers to changes in [[gene]] expression that are stable between [[cell (biology)|cell]] [[mitosis|division]]s, and sometimes between generations, but do not involve changes in the underlying [[DNA]] sequence of the organism.<ref>{{cite journal| title=Perceptions of epigenetics| author=Adrian Bird| journal=Nature| volume=447| pages=396–398| year=2007| doi=10.1038/nature05913}} PMID 17522671</ref> The idea is that environmental factors can cause an organism's genes to behave (or "express themselves") differently, even though the genes themselves don't change.<ref>[http://www.prospect-magazine.co.uk/article_details.php?id=10140 Special report: 'What genes remember' by Philip Hunter | Prospect Magazine May 2008 issue 146<!-- Bot generated title -->]</ref> Epigenetic changes in [[eukaryotic]] biology are most elegantly illustrated by the process of [[morphogenesis|cellular differentiation]] where [[pluripotent]] [[stem cells]] become the various [[cell line]]s of the [[embryo]]. This process becomes stable by mechanisms which may include [[gene silencing|silencing]] of some [[gene]]s, removal of silencing marks on some other genes and permanently inactivating still other genes.<ref>{{cite journal| last = Reik| first = Wolf| authorlink =| coauthors = | title = Stability and flexibility of epigenetic gene regulation in mammalian development| journal = Nature| volume = 447| issue = May (online)| pages = 425-432| publisher =| location = | date = 2007-05-23| url = http://www.nature.com/nature/journal/v447/n7143/full/nature05918.html| doi = 10.1038/nature05918| id = | accessdate = 2008-04-05 }}</ref> ==The Molecular basis of epigenetics== The molecular basis of epigenetics involves modifications to [[DNA]] and the [[chromatin]] proteins that associate with it. Epigenetic states are inherited when cells divide, and although most of these states are considered dynamic over the course of development in multicellular organisms, some epigenetic features show transgenerational inheritance and are inherited from one generation to the next.<ref>{{cite journal| title=Paramutation: From Maize to Mice| author=V.L. Chandler| journal=Cell| volume=128| pages=641–645| year=2007 | doi = 10.1016/j.cell.2007.02.007 <!--Retrieved from CrossRef by DOI bot-->}}</ref> Specific epigenetic processes include [[paramutation]], [[bookmarking]], [[Imprinting (genetics)|imprinting]], [[gene silencing]], [[X-inactivation|X chromosome inactivation]], [[position effect]], [[reprogramming]], [[transvection (genetics)|transvection]], [[maternal effect]]s, the progress of [[carcinogenesis]], many effects of [[teratogen]]s, 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]]). ==Etymology and definitions== The word "epigenetics" has been associated with many different definitions, and much of the confusion surrounding the use of the word "epigenetics" relates to the fact that it was originally defined to explain phenomena without knowing their molecular basis and with time became narrowly linked to certain phenomena as their molecular basis was discovered.<ref>Roloff, T.C., Nuber, U.A., 2005 Chromatin , epigenetics and stem cells. Eur J Cell Biol. 84, 123-135</ref> The word "epigenetics" (as in "[[epigenetic landscape]]") was coined by [[Conrad Hal Waddington|C. H. Waddington]] in 1942 as a [[portmanteau]] of the words "[[genetics]]" and "[[Epigenesis (biology)|epigenesis]]".<ref name=waddington>{{cite journal|author=C.H. Waddington (1942)| title=The epigenotype| journal=Endeavour| volume=1| pages=18–20}}</ref> Epigenesis is an older word used to describe the differentiation of cells from a [[totipotent]] state in embryonic development (used in contrast to "preformationism"). At the time Waddington first used the term "epigenetics," the physical nature of genes and their role in heredity was not known. Epigenetics was Waddington's model of how genes within a multicellular organism interact with their surroundings to produce a [[phenotype]]. Because all cells within an organism inherit the same DNA sequences, [[cellular differentiation]] processes crucial for epigenesis rely strongly on epigenetic rather than genetic inheritance. [[Robin Holliday]] defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."<ref>Holliday, R., 1990. Mechanisms for the control of gene activity during development. Biol. Rev. Cambr. Philos. Soc. 65, 431-471</ref> Thus, the word "epigenetic" can be used to describe any aspect other than DNA sequence that influences the development of an organism. Another usage of the word "epigenetics" was employed by the psychologist [[Erik Erikson]], who developed an "epigenetic theory of human development," which focuses on psycho-social crises. The modern usage of the word "epigenetic" is usually more narrow, referring to heritable traits (over rounds of cell division and sometimes transgenerationally) that do not involve changes to the underlying DNA sequence.<ref>Russo, V.E.A., Martienssen, R.A., Riggs, A.D., 1996 Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Plainview, NY.</ref> The Greek prefix "epi-" in the word "epigenetics" implies features that are "on top of" or "in addition to" genetics, and the current usage of the word reflects this&mdash;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&mdash;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 hypothesis|histone code]] or [[DNA methylation]] patterns. ==Mechanisms== Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:<ref name="jablonka92">{{cite journal | last = Jablonka | first = E | coauthors = Lamb MJ and Lachmann M | title = Evidence, mechanisms and models for the inheritance of acquired characteristics | journal = J. Theoret. Biol. | year = 1992 | month = September | volume = 158 | issue = 2 | pages = 245&ndash;268 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WMD-4KFTYG9-8&_user=10&_handle=C-WA-A-E-E-MsSAYWW-UUW-U-U-E-U-U-AAZEEUZCDZ-AAZDVYDBDZ-ADYZVZWEA-E-U&_fmt=summary&_coverDate=09%2F21%2F1992&_rdoc=8&_orig=browse&_srch=%23toc%236932%231992%23998419997%23628456!&_cdi=6932&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=56159ca247a23a908a55cdabe8dd69e7 | doi = 10.1016/S0022-5193(05)80722-2}}</ref> ===DNA methylation and chromatin remodeling=== [[Image:Nucleosome 1KX5 2.png|thumb|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 (genetics)|transcription states]] can give rise to epigenetic effects. There are several layers of regulation of [[gene expression]], one of which is remodeling of chromatin, the complex of DNA and the [[histone]] proteins with which it associates. Chromatin remodeling is initiated by one of two things: # [[posttranslational modification]] of the amino acids that make up histone proteins, # or the addition of methyl groups to the DNA, at [[CpG site]]s, to convert cytosine to [[5-methylcytosine]]. Whereas DNA is not completely stripped of [[nucleosome]]s during replication, it is possible that the remaining modified histones may act as templates, initiating identical modification of surrounding new histones after deposition. DNA methylation has a more clear method of propagation through the preferential methylation of hemimethylated symmetric sites by enzymes like Dnmt 1. Although modifications occur throughout the histone sequence, the unstructured termini of histones (called histone tails) are particularly highly modified. These modifications include [[acetylation]], [[methylation]] and [[ubiquitylation]]. 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 lysine normally has a positive charge on the nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone and prevent them from repelling each other. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge causing the DNA to repel itself. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA, thus opening it up and exposing it to enzymes like [[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&mdash;a protein segment (domain) that specifically binds acetyl-lysine&mdash;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 [[Heterochromatin Protein 1|HP1]] recruits HP1 to K9 methylated regions. One example that seems to refute the biophysical model for acetylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail. It should be emphasized that differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently than acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the [[histone code]]. DNA methylation frequently occurs in repeated sequences, and may help to suppress '[[junk DNA]]':<ref name="chedin92">{{cite web | last = Chédin | first = F | title = The Chedin Laboratory | year = 1992 | url = http://www.mcb.ucdavis.edu/faculty-labs/chedin/research.htm | accessdate=2006-12-28}}</ref> 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.<ref name="li92">{{cite journal | last = Li | first = E | coauthors = Bestor TH and Jaenisch R | title = Targeted mutation of the DNA methyltransferase gene results in embryonic lethality | journal = Cell | year = 1992 | month = June | volume = 69 | issue = 6 | pages = 915&ndash;926 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4D57093-1R&_coverDate=06%2F12%2F1992&_alid=515191593&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=7051&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=19d33f62482a44052266e684682a06da | doi = 10.1016/0092-8674(92)90611-F}}</ref> DNMT1 is the most abundant methyltransferase in somatic cells,<ref name="robertson99">{{cite journal | last = Robertson | first = KD | coauthors = Uzyolgi E, Lian G et al | title = The human DNA methyltransferases (DNMTs) 1, 3a, 3b: Coordinate mRNA expression in normal tissues and overexpression in tumors | journal = Nucleic Acids Res | year = 1999 | month = June | volume = 27 | issue = 11 | pages = 2291&ndash;2298 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10325416 | doi = 10.1093/nar/27.11.2291 | pmid = 10325416}}</ref> localizes to replication foci,<ref name="leonhardt92">{{cite journal | last = Leonhardt | first = H | coauthors = Page AW, Weier HU, Bestor TH | title = A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei | journal = Cell | year = 1992 | month = November | volume = 71 | issue = 5 | pages = 865&ndash;873 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4D0YB27-19&_coverDate=11%2F27%2F1992&_alid=515194074&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=7051&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9bdfefee567ff4ea6226007214ffbc34 | doi = 10.1016/0092-8674(92)90561-P}}</ref> has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).<ref name="chuang97">{{cite journal | last = Chuang | first = LS | coauthors = Ian HI, Koh TW et al | title = Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1 | journal = Science | year = 1997 | month = September | volume = 277 | issue = 5334 | pages = 1996&ndash;2000 | doi = 10.1126/science.277.5334.1996 | pmid = 9302295}}</ref> 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.<ref name="robertson00">{{cite journal | last = Robertson | first = KD | coauthors = Wolffe AP | title =DNA methylation in health and disease | journal = Nat Rev Genet | year = 2000 | month = October | volume = 1 | issue = 1 | pages = 11&ndash;19 | url = http://www.nature.com/nrg/journal/v1/n1/abs/nrg1000_011a_fs.html | doi =10.1038/35049533}}</ref> DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.<ref name="li92" /><ref name="li93">{{cite journal | last = Li | first = E | coauthors = Beard C and Jaenisch R | title =Role for DNA methylation in genomic imprinting | journal = Nature | year = 1993 | month = December | volume = 366 | issue = 6453 | pages = 362&ndash;365 | doi = 10.1038/366362a0}}</ref> 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 [http://cmol.nbi.dk/models/epigen/Epigen.html here] <ref> 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.</ref> . 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.<ref>Mark Ptashne, 2007. On the use of the word ‘epigenetic’. ''Current Biology'', '''17'''(7):R233-R236. {{doi|10.1016/j.cub.2007.02.030}}</ref> 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 [[promoter]]s.<ref name=Morris>{{cite book |chapterurl=http://www.horizonpress.com/rnareg|author= Morris KV|year=2008|chapter=Epigenetic Regulation of Gene Expression|title=RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity|publisher=Caister Academic Press|id=[http://www.horizonpress.com/rnareg ISBN 978-1-904455-25-7]}}</ref> ===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. Other epigenetic changes are mediated by the production of different [[Splicing (genetics)|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.<ref name="choi06">{{cite web | author= Choi CQ | title=The Scientist: RNA can be hereditary molecule | publisher = The Scientist | url=http://www.the-scientist.com/news/display/23494 | date=2006-05-25| accessdate=2006}}</ref> ===Prions=== {{details|Prions}} [[Prion]]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 [[Transmissible spongiform encephalopathy|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.<ref>{{cite journal| title=Epigenetic inheritance and prions| author=A. Yool and W.J. Edmunds| journal=Journal of Evolutionary Biology| year=1998| pages=241–242| volume=11 | doi = 10.1007/s000360050085 <!--Retrieved from CrossRef by DOI bot-->}}</ref> [[Fungal prion]]s are considered epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. [[PSI (prion)|PSI+]] and URE3, discovered in [[Saccharomyces cerevisiae|yeast]] in 1965 and 1971, are the two best studied of this type of prion.<ref>{{cite journal|title=[PSI], a cytoplasmic suppressor of super-suppression in yeast| author=B.S. Cox| journal=Heredity| volume=20| pages=505–521| year=1965 | doi = 10.1038/hdy.1965.65 <!--Retrieved from CrossRef by DOI bot-->}}</ref><ref>{{cite journal|title=Non-Mendelian mutation allowing ureidosuccinic acid uptake in yeast| author=F. Lacroute| journal=Journal of Bacteriology| volume=106| pages=519–522| year=1971}}</ref> 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.<ref>{{cite journal|title=Extrachromosomal psi+ determinant suppresses nonsense mutations in yeast|author=S.W. Liebman and F. Sherman| journal=Journal of Bacteriology| year=1979| volume=139| issue=3| pages=1068–1071}} [http://jb.asm.org/cgi/content/abstract/139/3/1068 Free full text available]</ref> 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.<ref>{{cite journal| title=A yeast prion provides a mechanism for genetic variation and phenotypic diversity| author=H.L. True and S.L. Lindquist| journal=Nature| year=2000| volume=407| pages=477–483 | doi = 10.1038/35035005 <!--Retrieved from CrossRef by DOI bot-->}}</ref><ref>{{cite journal| title=Prions as adaptive conduits of memory and inheritance| author=J. Shorter and S. Lindquist| journal=Nature Reviews Genetics| volume=6| issue=6| pages=435–450| year=2005 | doi = 10.1038/nrg1616 <!--Retrieved from CrossRef by DOI bot-->}}</ref> ===Structural inheritance systems=== {{details|Structural inheritance}} In [[ciliate]]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.<ref>{{cite book |title=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 }}</ref> ==Functions and consequences== ===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, [[morphogen]]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 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.<ref>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}}</ref> ===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, but are unusually common because individuals are essentially [[hemizygous]] because of [[Genomic Imprinting|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.<ref>{{OMIM|105830}}</ref> ===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]].<ref>{{cite book |first=Eva |last=Jablonka |authorlink=Eva Jablonka |coauthors=Marion J. Lamb |title=Evolution in Four Dimensions |publisher=MIT Press |year=2005 |id=ISBN 0-262-10107-6}}</ref><ref>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 (journal)|Nature]] '''435''', 565-566 (2 June 2005)</ref> 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.<ref name=rando_and_verstrepen>{{cite journal| author=O.J. Rando and K.J. Verstrepen| title=Timescales of Genetic and Epigenetic Inheritance| journal=Cell| volume=128| pages=655–668| year=2007 | doi = 10.1016/j.cell.2007.01.023 <!--Retrieved from CrossRef by DOI bot-->}}</ref> Whereas the DNA sequence of the region is not mutated, this change is reversible. It has also been speculated that organisms may take advantage of differential mutation rates associated with epigenetic features to control the mutation rates of particular genes.<ref name=rando_and_verstrepen /> Epigenetic changes have also been observed to occur in response to environmental exposure&mdash;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.<ref>{{cite journal| author=Cooney, CA, Dave, AA, and Wolff, GL| title=Maternal Methyl Supplements in Mice Affect Epigenetic Variation and DNA Methylation of Offspring| year=2002| journal=Journal of Nutrition| volume=132| pages=2393S–2400S}}[http://jn.nutrition.org/cgi/content/full/132/8/2393S available online]</ref><ref name="waterland">{{cite journal| author= Waterland RA and Jirtle RL| title = Transposable elements: Targets for early nutritional effects on epigenetic gene regulation| journal = Molecular and Cellular Biology| year = 2003| month = August| volume = 23| issue = 15| pages = 5293–5300| url = http://mcb.asm.org/cgi/content/full/23/15/5293 | doi = 10.1128/MCB.23.15.5293-5300.2003 <!--Retrieved from CrossRef by DOI bot-->| pmid = 12861015}}</ref> ==Epigenetic effects in humans== === Genomic imprinting and related disorders === Some human disorders are associated with genomic imprinting, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their germ cells.<ref>{{cite journal| title=Genomic imprinting in mammals: Emerging themes and established theories| author=A.J. Wood and A.J. Oakey| journal=PLOS Genetics| volume=2| issue=11| year=2006| pages=1677–1685 | doi = 10.1371/journal.pgen.0020147 <!--Retrieved from CrossRef by DOI bot-->}} [http://genetics.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pgen.0020147 available online]</ref> The most well-known case of imprinting in human disorders is that of [[Angelman syndrome]] and [[Prader-Willi syndrome]]&mdash;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.<ref>{{cite journal| title=Angelman and Prader-Willi syndromes share a common chromosome deletion but differ in parental origin of the deletion| author=J.H.M. Knoll, R.D. Nicholls, R.E. Magenis, J.M. Graham Jr, M. Lalande, S.A. Latt| journal=American Journal of Medical Genetics| volume=32| pages=285–290| year=1989 | doi = 10.1002/ajmg.1320320235 <!--Retrieved from CrossRef by DOI bot-->}}</ref> This is due to the presence of [[Genomic Imprinting|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. ===Transgenerational epigenetic observations=== Marcus Pembrey and colleagues also observed that the paternal (but not maternal) grandsons of Swedish boys who were exposed to famine in the 19th century were 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.<ref>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 [http://www.dundee.ac.uk/externalrelations/events/lectures.html lecture]; see also discussion at [[Leeds University]], [http://www.fbs.leeds.ac.uk/staff/pm/epigenetics.htm#exciting2 here]</ref> === Cancer and developmental abnormalities === A variety of compounds are considered as epigenetic [[carcinogens]]&mdash;they result in an increased incidence of tumors, but they do not show [[mutagenic|mutagen]] activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include [[diethylstilbestrol]], [[arsenite]], [[hexachlorobenzene]], and [[nickel]] compounds. Many teratogens exert specific effects on the fetus by epigenetic mechanisms.<ref name="bishop97">{{cite journal | last = Bishop | first = JB | coauthors = Witt KL and Sloane RA | title = Genetic toxiticities of human teratogens | journal = Mutat Res | year = 1997 | month = December | volume = 396 | issue = 1-2 | pages = 9&ndash;43 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2C-3TGW0WR-19&_coverDate=12%2F12%2F1997&_alid=515200131&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4915&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=991625903beeedc77a9455d6fa2382a9}}</ref><ref name="gurvich04">{{cite journal | last = Gurvich | first = N | coauthors = Berman MG, Wittner BS et al | title = Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo | journal = FASEB J | year = 2004 | month = July | volume = 19 | issue = 9 | pages = 1166&ndash;1168 | url = http://www.fasebj.org/cgi/reprint/04-3425fjev1 | doi = 10.1096/fj.04-3425fje | pmid = 15901671}}</ref> 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.<ref name="smithells98">{{cite journal | last = Smithells | first = D |title = Does thalidomide cause second generation birth defects? | journal = Drug Saf | year = 1998 | month = November | volume = 19 | issue = 5 | pages = 339&ndash;341 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9825947 |doi = 10.2165/00002018-199819050-00001}}</ref> However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.<ref name="friedler96">{{cite journal | last = Friedler | first = G | title = Paternal exposures: impact on reproductive and developmental outcome. An overview. | journal = Pharmacol Biochem Behav | year = 1996 | month = December | volume = 55 | issue = 4 | pages = 691&ndash;700 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8981601 | doi = 10.1016/S0091-3057(96)00286-9}}</ref> [http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf FDA label information] for Vidaza(tm), a formulation of [[5-azacytidine|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.<ref name="cicero91">{{cite journal | last = Cicero | first = TJ | coauthors = Adams NL, Giodarno A et al | title = Influence of morphine exposure during adolescence on the sexual maturation of male rats and the development of their offspring | journal = J Pharmacol Exp Ther. | year = 1991 | month = March | volume = 256 | issue = 3 | pages = 1086&ndash;1093 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2005573}}</ref> In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.<ref name="newbold06">{{cite journal | last = Newbold | first = RR | coauthors = Padilla-Banks E and Jefferson WN | title = Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations | journal = Endocrinology | year = 2006 | month = June | volume = 147 | issue = 6 Suppl | pages = S11&ndash;S17 | doi = 10.1210/en.2005-1164 | pmid = 16690809}}</ref> == 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 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.<ref name="Casadesus">{{cite journal| author= Casadesus J and Low D| title = Epigenetic Gene Regulation in the Bacterial World| journal = Microbiol Mol Biol Rev| year = 2006| month = September| volume = 70| issue = 3| pages = 830–856 | doi = 10.1128/MMBR.00016-06 <!--Retrieved from CrossRef by DOI bot-->}}</ref> <ref name=JorgTost>{{cite book | author = Tost J (editor). | title = Epigenetics | publisher = Caister Academic Press | year = 2008 | url=http://www.horizonpress.com/epi | id = [http://www.horizonpress.com/epi ISBN 978-1-904455-23-3 ]}}</ref> 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.<ref name=JorgTost>{{cite book | author = Tost J (editor). | title = Epigenetics | publisher = Caister Academic Press | year = 2008 | url=http://www.horizonpress.com/epi | id = [http://www.horizonpress.com/epi ISBN 978-1-904455-23-3 ]}}</ref> == See also == * [[Histone code]] * [[Baldwinian evolution]] * [[Barbara McClintock]] * [[Centromere]] * [[Evolutionary developmental psychology]] * [[Molecular biology]] * [[Somatic epitype]] * [[Weismann barrier]] == Further reading == <!-- Dead note "Jablonka2002": Eva Jablonka and Marion J. Lamb. The Changing Concept of Epigenetics. ''Annals of the New York Academy of Sciences'' '''981''':82-96 (2002). --> *[[Oskar Hertwig]], 1849-1922. ''Biological problem of today: preformation or epigenesis? The basis of a theory of organic development''. W. Heinemann: London, 1896. * R. 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 epigenotype". ''Endeavour'' '''1''', 18&ndash;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 * [http://www.uq.edu.au/biohumanities/webpdfs/moleculardevelop.pdf 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. *[[Survival of the Sickest (book)|Survival of the Sickest]] by Sharon Moalem with Jonathan Prince, Published 2007 *[http://www.horizonpress.com/epi Epigenetics] edited by J. Tost. Caister Academic Press, 2008. *[http://www.horizonpress.com/rnareg RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity] edited by K. V. Morris. Caister Academic Press, 2008. == Notes and references == {{Reflist|2}} ==External links== <!--===========================({{NoMoreLinks}})===============================--> <!--| DO NOT ADD MORE LINKS TO THIS ARTICLE. WIKIPEDIA IS NOT A COLLECTION OF |--> <!--| LINKS. 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