Jump to content

Epigenetics

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by NBeale (talk | contribs) at 20:32, 21 May 2007 (→Philosophical implications: Wikilink Jorgensen). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

In Biology, epigenetics is the study of all heritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA[1]. When a cell undergoes an epigenetic change, it is the phenotype of the cell that is affected. Epigenetic events during embryo development lead to the differentiation of fetal cells. The combined processes of fetal development and cell differentiation are called epigenesis. The term is also sometimes used as a synonym for the closely related topic of chromatin remodeling.

Epigenetics is distinct from genetics, which focuses on how traits are inherited in genes (and associated DNA sequences), because in epigenetic inheritance the DNA sequence itself is not changed.[2]. Recent research demonstrates that organisms have evolved mechanisms to influence the timing or genomic location of heritable variability. Hypervariable contingency loci and epigenetic switches increase the variability of specific phenotypes; error-prone DNA replicases produce bursts of variability in times of stress. It appears that these mechanisms tune the variability of a given phenotype to match the variability of the acting selective pressure. Although these observations do not undermine Darwin's theory, they suggest that selection and variability are less independent than once thought.[3]

Epigenetics is distinct from epigenesis, which is the long-accepted description of embryonic morphogenesis as a gradual process of increasing complexity, in which organs are formed de novo (as opposed to preformationism). However, because all of the cells in the body inherit the same DNA sequences (with a few exceptions, such as B cells), cellular differentiation processes crucial for epigenesis rely almost entirely on epigenetic rather than genetic inheritance from one cell generation to the next. If this were not so, then somatic cell cloning would be impossible, because a normal organism couldn't be recovered from a differentiated cell nucleus and reprogrammed to become totipotent.

Epigenetics includes the study of effects that are inherited from one cell generation to the next whether these occur in embryonic morphogenesis, regeneration, normal turnover of cells, tumors, cell culture, or the replication of single celled organisms. Recently, there has been increasing interest in the idea that some forms of epigenetic inheritance may be maintained even through the production of germ cells (meiosis), and therefore may endure from one generation to the next in multicellular organisms.[4]

Specific epigenetic processes of interest 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 histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.

The epigenome

The epigenome is the overall epigenetic state of a cell. As one embryo can generate a multitude of cell fates during development, one genome could be said to give rise to many epigenomes. The epigenetic code is hypothesized to be a defining code in every eukaryotic cell consisting of the specific epigenetic modification in each cell. Taken to its extreme, this represents 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.

Mechanisms

Several types of epigenetic inheritance systems may play a role in what has become known as cell memory [5]:

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 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. [6]

Structural inheritance systems

Further information: 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 [citation needed].

DNA methylation and chromatin remodelling

DNA associates with histone proteins to form chromatin.

Since the phenotype of a cell or individual is affected by which of its genes it transcribes, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression, one of which is remodelling of chromatin, the complex of DNA and the histone proteins with which it associates. Chromatin remodelling is initiated by one of two things:

  1. posttranslational modification of the amino acids that make up histone proteins,
  2. or the addition of methyl groups to the DNA, at CpG sites, to convert cytosine to 5-methylcytosine.

Since DNA is not completely stripped of nucleosomes during replication, it is possible that the remaining modified histones may act as templates, initiating identical modification of surrounding new histones after deposition. However, since chromatin and DNA modifications are linked, and it is known that DNA methylation patterns are maintained after DNA replication, DNA methylation is a more likely mechanism by which chromatin structure is inherited.

While 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 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. Since lysine normally has a positive charge on the nitrogen at its end, it can bind the negatively charged phosphates of the DNA backbone and prevent them from repelling each other. 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—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 with 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 histone code.

DNA methylation frequently occurs in repeated sequences, and may help to suppress 'junk DNA'. [7]: 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 [8]. DNMT1 is the most abundant methyltransferase in somatic cells [9], localizes to replication foci [10], has a 10-40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA) [11]. 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 [12]. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation [8] [13].

Because DNA methylation and chromatin remodelling 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, as chromatin remodelling is not always inherited, and not all epigenetic inheritance involves chromatin remodelling.[14]

Prions

Further information: Prions

Infectious diseases are not typically described as epigenetic regulators, although infection and vertical transmission of viruses such as HIV works in a similar way. However, some prions (such as fungal prions) have been shown to be beneficial, and since they describe the adaptive function of a protein, they are described as an epigenetic inheritance mechanism.

Maternal conditioning of the immune system

Another important mechanism of epigenetic inheritance is the the conditioning of the embryonic immune system by the mother, which has significant impact on survival and which is a function of the particular evolutionary dynamics of somatic hypermutation and selection of antibodies rather than normal genetic evolution[15]

Functions and consequences

Development

Somatic epigenetic inheritance, particularly through DNA methylation and chromatin remodelling, 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".

Evolution

Germ-line epigenetic inheritance is reminiscent of earlier theories of the inheritance of acquired characters (Lamarckism or Darwin's speculations on pangenesis). However, unlike earlier theories, epigenetics accepts the overriding importance of both natural selection and of the alteration of the DNA genome by random mutation. For example, once a portion of the foregut is exposed to secretions from cardiogenic mesoderm, its cells become liver cells, and this acquired characteristic is then passed on to subsequent generations of cells. However, the amount of information transmitted epigenetically is limited: it is probably not possible by epigenetic means to create a "half liver/ half intestine" cell that breeds true from one cell generation to the next, nor is it necessarily possible to activate or deactivate the expression of any particular gene by epigenetic means.

The ability of a cell to take on and maintain a "liver" identity reflects a long history of natural selection to make that an inducible and stable phenotype. Because only some of the physiological responses of the cell to a stimulus will lead to heritable epigenetic changes, the physiological changes seen in daughter cells do not necessarily need to be the same as those seen in the parental cell. Even if adaptive epigenetic changes can be shown to be inherited from one generation of organisms to the next, they must still arise as regulatory mechanisms encoded by the genome and in response to natural selection, and they will likely be transient and eventually reversible unless they induce a specific mutation within the genome.

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, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.[16]

Transgenerational epigenetic effects in humans

Work by Marcus Pembrey indicates that two distinct genetic conditions -- Angelman syndrome and Prader-Willi syndrome -- appear to be produced by the same genetic mutation, chromosome 15q partial deletion, and that the particular syndrome that will develop seems to depend on whether the mutation is inherited from the child's mother or from their father. Since the conventional genome would seem to be the same in either case, this suggests that some inherited traits may depend on information that exists outside the "conventional" genome.

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 nickel compounds.

Many teratogens exert specific effects on the fetus by epigenetic mechanisms. [17] [18] 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. [19] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.[20] 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. [21] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms [22].

Philosophical implications

The philosophical implications of epigenetics have been discussed by scientists such as Eva Jablonka[23] and Massimo Pigliucci,[24] who cite epigenetic inheritance as one of a number of factors suggesting that the neo-darwinian synthesis of the early twentieth century is incomplete.[25] The extent to which evolution operates at several different levels is the nub of Patrick Bateson's "friendly disagreement" with Richard Dawkins.[26]. In a critique of determinism Robert Winston suggests that epigenetic inheritance is an important factor in the inadequacy of the "selfish gene" and "DNA" metaphors.[27][28]

Contemporary admirers of Wolfgang Pauli point to epigenetic inheritance as vindications of his repeated criticisms of neo-Darwinian positions in evolutionary biology.[29]

Etymology

The term epigenetics has over time been used in various senses, in part because the Greek prefix ep? (epi-) has at least six meanings in English (including 'on', 'after' and 'in addition'), but also because various theories of epigenetic development, inheritance, and evolution have been proposed.

Some biologists at one time believed that genetics, which seemed to postulate a one-to-one correspondence between genotype and phenotype, could not explain cell differentiation. They developed a theory that each undifferentiated cell underwent a crisis that determined its fate, which was not inherent in its genes, and was therefore (borrowing from the Greek ep?) epigenetic.

The psychologist Erik Erikson developed an epigenetic theory of human development which focuses on psycho-social crises. In Erikson's view, each individual goes through several developmental stages, the transition between each of which is marked by a crisis. According to the theory, although the stages are largely predetermined by genetics, the manner in which the crises are resolved is not; by analogy with the epigenetic theory of cell differentiation, the process was said to be epigenetic.

The biologist C.H. Waddington is sometimes credited with coining the term epigenetics in 1942, when he defined it as “the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being”. However the term "epigenesis" has been used since the early eighteenth century. (see also Pierre Louis Maupertuis)

Epigenetic inheritance is the transmission of information from a cell or multicellular organism to its descendants without that information being encoded in the nucleotide sequence of the gene.

See also

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.
  • 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.
  • 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 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

Notes & references

  1. ^ Definition given in the Peter Mayer Lab at Leeds University
  2. ^ Griffiths et. al., Modern Genetic Analysis WH Freeman 1999 Ch 14 Online at NIH here
  3. ^ Rando OJ and Verstrepen KJ. Cell 2007 Feb 23;128(4):655-68.
  4. ^ Waterland, RA (2003). "Transposable elements: Targets for early nutritional effects on epigenetic gene regulation". Mol Cell Biol. 23 (15): 5293–5300. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  5. ^ Jablonka, E (1992). "Evidence, mechanisms and models for the inheritance of acquired characteristics". J. Theoret. Biol. 158 (2): 245–268. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  6. ^ Choi CQ (2006-05-25). "The Scientist: RNA can be hereditary molecule". The Scientist. Retrieved 2006. {{cite web}}: Check date values in: |accessdate= (help)
  7. ^ Chédin, F (1992). "The Chedin Laboratory". Retrieved 2006-12-28.
  8. ^ a b Li, E (1992). "Targeted mutation of the DNA methyltransferase gene results in embryonic lethality". Cell. 69 (6): 915–926. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  9. ^ Robertson, KD (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  10. ^ Leonhardt, H (1992). "A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei". Cell. 71 (5): 865–873. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  11. ^ Chuang, LS (1997). "Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1". Science. 277 (5334): 1996–2000. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  12. ^ Robertson, KD (2000). "DNA methylation in health and disease". Nat Rev Genet. 1 (1): 11–19. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  13. ^ Li, E (1993). "Role for DNA methylation in genomic imprinting". Nature. 366 (6453): 362–365. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  14. ^ Mark Ptashne, 2007. On the use of the word ‘epigenetic’. Current Biology, 17(7):R233-R236. doi:10.1016/j.cub.2007.02.030
  15. ^ see eg Ch 10 of The Implicit Genome eg Linda Caporale, Oxford: OUP (2006) ISBN 9780195172706
  16. ^ Online Mendelian Inheritance in Man (OMIM): 105830
  17. ^ Bishop, JB (1997). "Genetic toxiticities of human teratogens". Mutat Res. 396 (1–2): 9–43. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  18. ^ Gurvich, N (2004). "Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo". FASEB J. 19 (9): 1166–1168. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  19. ^ Smithells, D (1998). "Does thalidomide cause second generation birth defects?". Drug Saf. 19 (5): 339–341. {{cite journal}}: Unknown parameter |month= ignored (help)
  20. ^ Friedler, G (1996). "Paternal exposures: impact on reproductive and developmental outcome. An overview". Pharmacol Biochem Behav. 55 (4): 691–700. {{cite journal}}: Unknown parameter |month= ignored (help)
  21. ^ Cicero, TJ (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  22. ^ Newbold, RR (2006). "Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations". Endocrinology. 147 (6 Suppl): S11–S17. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  23. ^ Eva Jablonka and Marion J. Lamb Evolution in Four Dimensions MIT Press 2005 p6 & 7
  24. ^ Massimo Pigliucci reviewing Jablonka & Lamb op cit., in Nature 435, 565-566
  25. ^ The book Evolution in Four Dimensions is published by the MIT Press in their "Life and Mind: Philosophical Issues in Biology and Psychology" series. Massimo Pigliucci is Affiliate Faculty, Department of Philosophy, SUNY-Stony Brook
  26. ^ Patrick Bateson's chapter "The Nest's Tale: Affectionate Disagreements with Richard Dawkins" in Richard Dawkins: How a Scientist Changed the Way We Think
  27. ^ Robert Winston Greatest Minds "The Science Delusion" Lecture at the University of Dundee
  28. ^ Robert Winston interview in The Guardian April 25, 2007 - note however that this brief piece in the Guardian does not refer to the comments on epigenetics which occur in Winston's lecture
  29. ^ Conference on Wolfgang Pauli's Philosophical Ideas and Contemporary Science organised by ETH May 20 - 25, 2007. The abstract of a paper discussing this by Richard Jorgensen is here
Retrieved from "https://en.wikipedia.org/w/index.php?title=Epigenetics&oldid=132518191"