biology, the term epigenetics refers to changes in gene expressioncaused by mechanisms other than changes in the underlying DNAsequence. 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 DNAsequence of the organism, [cite journal| title=Perceptions of epigenetics| author=Adrian Bird| journal=Nature| volume=447| pages=396–398| year=2007| doi=10.1038/nature05913 PMID 17522671] instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently. [ [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 ] ] The best example of epigenetic changes in eukaryoticbiology is the process of cellular differentiation. During morphogenesis, totipotent stem cellsbecome the various pluripotent cell lines of the embryowhich 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 et cetera as it continues to divide. It does so by activating some genes while inhibiting others. [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 ]
Etymology and definitions
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. [Roloff, T.C., Nuber, U.A., 2005 Chromatin , epigenetics and stem cells. Eur J Cell Biol. 84, 123-135]
"Epigenetics" (as in "
epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteauof the words " genetics" and "epigenesis".cite journal|author=C.H. Waddington (1942)| title=The epigenotype| journal=Endeavour| volume=1| pages=18–20|doi=10.1016/0160-9327(77)90005-9|year=1977] "Epigenesis" (see contrasting principle of " preformationism") is an older word to describe the differentiation of cells from their initial totipotentstate 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 Hollidaydefined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms." [Holliday, R., 1990. Mechanisms for the control of gene activity during development. Biol. Rev. Cambr. Philos. Soc. 65, 431-471] 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 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. [Russo, V.E.A., Martienssen, R.A., Riggs, A.D., 1996 Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Plainview, NY.] 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; 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 methylationpatterns.
"Epigenetic" was also used by the psychologist
Erik Eriksonin his Psychosocial developmenttheory, however that usage is of primarily historical interest. [ [http://www.bio-medicine.org/biology-definition/Epigenetics/ Epigenetics ] ]
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 chromatinproteins associated with DNA may be activated or silenced. What this means is that every cell in your body has the same instruction manual, but different cell types are using different chapters. For example, your neurons contain the DNA instructions to make your fingernails, but for these and most other cell in the body, the necessary genes are turned off. 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. [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 ] Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histonemodifications and heterochromatin, and technical limitations affecting parthenogenesisand 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-chipand ChIP-seq), fluorescent in situ hybridization, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification ( DamID) and bisulfite sequencing. Furthermore, the use of bioinformaticmethods is playing an increasing role ( computational epigenetics).
Several types of epigenetic inheritance systems may play a role in what has become known as cell memory: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 = 245–268
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]
DNA methylation and chromatin remodeling
phenotypeof 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 histoneproteins 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 initiated by one of two things:
# The first way is
post translational modificationof the amino acids that make up histone proteins. Histone proteins are made up of long chains of amino acids. If you change the amino acids that are in the chain, you can change the shape of the histone sphere. 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 way. By altering the shape of the histones around it, these modified histones would ensure that a differentiated cell would STAY differentiated, and not convert back into being a stem cell.
# The second way is the addition of methyl groups to the DNA, at
CpG sites, to convert cytosine to 5-methylcytosine. Cytosine is the nucleotide that our cells can "read." Our cells cannot "read" methylcytosine. If you think of your DNA as an instruction manual again, changing cytosine to methylcytosine is like changing the font on your word document to " wingdings." Since the cell can no longer "read" the gene, the gene is turned off.Fact|date=October 2008
The way that the cells stay differentiated in the case of DNA methylation is more clear to us than it is in the case of histone shape. Basically, certain enzymes (such as Dnmt1) "prefer" the methylated cytosine. If this enzyme comes to a "hemimethylated" portion of DNA (DNA where only one strand contains the methylcytosine, and the other side still contains cytosine) the enzyme will methylate the other half.
Although modifications occur throughout the histone sequence, the unstructured termini of histones (called histone tails) are particularly highly modified. These modifications include
acetylation, methylationand ubiquitylation. 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 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 polymeraseso 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 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
DNA methylation frequently occurs in repeated sequences, and may help to suppress '
junk DNA':cite web
last = Chédin
first = F
title = The Chedin Laboratory
year = 1992
url = http://www.mcb.ucdavis.edu/faculty-labs/chedin/research.htm
5-methylcytosineis chemically very similar to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islandswhere they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylationpatterns 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.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 = 915–926
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] DNMT1 is the most abundant methyltransferase in somatic cells,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 = 2291–2298
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10325416
doi = 10.1093/nar/27.11.2291
pmid = 10325416] localizes to replication foci,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 = 865–873
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] has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).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 = 1996–2000
doi = 10.1126/science.277.5334.1996
pmid = 9302295] 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.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 = 11–19
url = http://www.nature.com/nrg/journal/v1/n1/abs/nrg1000_011a_fs.html
doi =10.1038/35049533] DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.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 = 362–365
doi = 10.1038/366362a0]
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] [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.] .
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. [Mark Ptashne, 2007. On the use of the word ‘epigenetic’. "Current Biology", 17(7):R233-R236. doi|10.1016/j.cub.2007.02.030]
It has been suggested that the
histone codecould 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.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] ]
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,
Hnf4and MyoDenhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factoractivity of the proteinsthey encode. 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 junctionsare important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygoteby the mother during oogenesisor 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.cite web
author= Choi CQ
title=The Scientist: RNA can be hereditary molecule
publisher = The Scientist
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. [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 ] 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. [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 ] [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] 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. [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] ] 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. [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 ] [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 ]
tructural inheritance systems
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. [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 ]
Functions and consequences
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 cellsretaining 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. [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]
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 syndromeand Prader-Willi syndrome. These are normal genetic diseases caused by gene deletions, but are unusually common because individuals are essentially hemizygousbecause 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. [OMIM|105830]
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
paramutationobserved 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. [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] [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)]
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.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 ] 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.
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. [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] ] 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 | pmid = 12861015]
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. [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 [http://genetics.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pgen.0020147 available online] ] The most well-known case of imprinting in human disorders is that of
Angelman syndromeand 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. [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 ] This is due to the presence of genomic imprinting in the region. Beckwith-Wiedemann syndromeis 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
diabetesmortality in the grandchildren increased, suggesting that this was a transgenerational epigenetic inheritance. [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 Winstonrefers 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] ]
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 diethylstilbestrol, arsenite, hexachlorobenzene, and nickelcompounds.
Many teratogens exert specific effects on the fetus by epigenetic mechanisms.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 = 9–43
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] 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 = 1166–1168
url = http://www.fasebj.org/cgi/reprint/04-3425fjev1
doi = 10.1096/fj.04-3425fje
pmid = 15901671] While epigenetic effects may preserve the effect of a teratogen such as
diethylstilbestrolthroughout 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.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 = 339–341
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] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.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 = 691–700
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] [http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf 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.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 = 1086–1093
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2005573] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.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–S17
doi = 10.1210/en.2005-1164
pmid = 16690809]
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.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 ]
yeast prionPSI 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.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 ] ]
Evolutionary developmental psychology
Synthetic genetic array
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, 18–20.
*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 Jablonkaand 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.
* [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
* [http://discovermagazine.com/2006/nov/cover DNA Is Not Destiny] - Discover Magazine cover story
* [http://www.bbc.co.uk/sn/tvradio/programmes/horizon/ghostgenes.shtml BBC - Horizon - 2005 - The Ghost In Your Genes]
* [http://www.hopkinsmedicine.org/press/2002/november/epigenetics.htm Epigenetics article] at Hopkins Medicine
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