Psychology Wiki


34,189pages on
this wiki
Revision as of 07:07, March 7, 2008 by Dr Joe Kiff (Talk | contribs)



For the unfolding of an organism or the theory that plants and animals develop in this way, see Epigenesis (biology).

Epigenetics is a term in biology used to refer to features such as chromatin and DNA modifications that are stable over rounds of cell division but do not involve changes in the underlying DNA sequence of the organism.[1] These epigenetic changes play a role in the process of cellular differentiation, allowing cells to stably maintain different characteristics despite containing the same genomic material. Epigenetic features are inherited when cells divide despite a lack of change in the DNA sequence itself and, although most of these features 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.[2]



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.[3]

The word "epigenetics" (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the words "genetics" and "epigenesis".[4] 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."[5] 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.[6] 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—epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.



Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:[7]

DNA methylation and chromatin remodeling

Nucleosome 1KX5 2

DNA associates with histone proteins to form chromatin.

Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression, one 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:

  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.

Whereas 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. DNA methylation has a more clear method of propagation through the preferential methylation of hemimethylated symmetric sites by enzymes like Dnmt 1.







DNA methylation frequently occurs in repeated sequences, and may help to suppress 'junk DNA':[8] 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.[9] DNMT1 is the most abundant methyltransferase in somatic cells,[10] localizes to replication foci,[11] has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).[12] 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.[13] DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.[9][14]

Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of states of larger chromosomal regions are often thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. A simplified stochastic model for this type of epigenetics is found here [15] .



RNA transcripts and their encoded proteins



For more details on this topic, see Prions.


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.[20][21] 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.[22] 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.[23][24]

Structural inheritance systems

For more details on this topic, see Structural inheritance.


Functions and consequences








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.[31][32] Although there is no reason to suspect that such a process is anything other than a product of genetics, and therefore orthodox evolutionary mechanisms, the observation of trans-generational epigenetic change occurring in response to environmental factors is reminiscent of the 19th century Lamarckian hypothesis of inheritance and evolution.

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.[33] The most well-known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndrome—both can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.[34] This is due to the presence of genomic imprinting in the region. Beckwith-Wiedemann syndrome is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.

Transgenerational epigenetic observations


Cancer and developmental abnormalities


Many teratogens exert specific effects on the fetus by epigenetic mechanisms.[36][37] 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.[38] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.[39] 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.[40] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.[41]

Epigenetics in microorganisms



See also

Further reading

  • Survival of the Sickest by Dr. Sharon Moalem with Jonathan Prince, Published 2007
  • Gene and Epigene - The Next Cancer Therapy?

Notes and references

  1. Adrian Bird (2007). Perceptions of epigenetics. Nature 447: 396-398. PMID 17522671
  2. V.L. Chandler (2007). Paramutation: From Maize to Mice. Cell 128: 641-645.
  3. Roloff, T.C., Nuber, U.A., 2005 Chromatin , epigenetics and stem cells. Eur J Cell Biol. 84, 123-135
  4. C.H. Waddington (1942). The epigenotype. Endeavour 1: 18-20.
  5. Holliday, R., 1990. Mechanisms for the control of gene activity during development. Biol. Rev. Cambr. Philos. Soc. 65, 431-471
  6. Russo, V.E.A., Martienssen, R.A., Riggs, A.D., 1996 Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Plainview, NY.
  7. Jablonka, E, Lamb MJ and Lachmann M (September 1992). Evidence, mechanisms and models for the inheritance of acquired characteristics. J. Theoret. Biol. 158 (2): 245–268.
  8. Chédin, F (1992). The Chedin Laboratory. URL accessed on 2006-12-28.
  9. 9.0 9.1 Li, E, Bestor TH and Jaenisch R (June 1992). Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69 (6): 915–926.
  10. Robertson, KD, Uzyolgi E, Lian G et al (June 1999). The human DNA methyltransferases (DNMTs) 1, 3a, 3b: Coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27 (11): 2291–2298.
  12. Chuang, LS, Ian HI, Koh TW et al (September 1997). Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 277 (5334): 1996–2000.
  13. Robertson, KD, Wolffe AP (October 2000). DNA methylation in health and disease. Nat Rev Genet 1 (1): 11–19.
  14. Li, E, Beard C and Jaenisch R (December 1993). Role for DNA methylation in genomic imprinting. Nature 366 (6453): 362–365.
  15. 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.
  16. Mark Ptashne, 2007. On the use of the word ‘epigenetic’. Current Biology, 17(7):R233-R236. DOI:10.1016/j.cub.2007.02.030
  17. Morris KV (2008). "Epigenetic Regulation of Gene Expression" RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity, Caister Academic Press. ISBN 978-1-904455-25-7.
  19. A. Yool and W.J. Edmunds (1998). Epigenetic inheritance and prions. Journal of Evolutionary Biology 11: 241-242.
  20. B.S. Cox (1965). [PSI], a cytoplasmic suppressor of super-suppression in yeast. Heredity 20: 505-521.
  21. F. Lacroute (1971). Non-Mendelian mutation allowing ureidosuccinic acid uptake in yeast. Journal of Bacteriology 106: 519-522.
  22. S.W. Liebman and F. Sherman (1979). Extrachromosomal psi+ determinant suppresses nonsense mutations in yeast. Journal of Bacteriology 139 (3): 1068-1071. Free full text available
  23. H.L. True and S.L. Lindquist (2000). A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407: 477-483.
  24. J. Shorter and S. Lindquist (2005). Prions as adaptive conduits of memory and inheritance. Nature Reviews Genetics 6 (6): 435-450.
  25. Oyama, Susan; Paul E. Griffiths, Russell D. Gray (2001). Cycles of Contingency: Developmental Systems and Evolution, MIT Press.
  26. 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
  27. OMIM 105830
  28. Jablonka, Eva; Marion J. Lamb (2005). Evolution in Four Dimensions, MIT Press. ISBN 0-262-10107-6.
  29. 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)
  30. 30.0 30.1 O.J. Rando and K.J. Verstrepen (2007). Timescales of Genetic and Epigenetic Inheritance. Cell 128: 655-668.
  31. Cooney, CA, Dave, AA, and Wolff, GL (2002). Maternal Methyl Supplements in Mice Affect Epigenetic Variation and DNA Methylation of Offspring. Journal of Nutrition 132: 2393S-2400S.available online
  32. Waterland RA and Jirtle RL (August 2003). Transposable elements: Targets for early nutritional effects on epigenetic gene regulation. Molecular and Cellular Biology 23 (15): 5293-5300.
  33. A.J. Wood and A.J. Oakey (2006). Genomic imprinting in mammals: Emerging themes and established theories. PLOS Genetics 2 (11): 1677-1685. available online
  34. J.H.M. Knoll, R.D. Nicholls, R.E. Magenis, J.M. Graham Jr, M. Lalande, S.A. Latt (1989). Angelman and Prader-Willi syndromes share a common chromosome deletion but differ in parental origin of the deletion. American Journal of Medical Genetics 32: 285-290.
  35. Pembrey ME, Bygren LO, Kaati G, et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006; 14: 159-66. PMID 16391557. Robert Winston refers to this study in a lecture; see also discussion at Leeds University, here
  36. Bishop, JB, Witt KL and Sloane RA (December 1997). Genetic toxiticities of human teratogens. Mutat Res 396 (1-2): 9–43.
  37. Gurvich, N, Berman MG, Wittner BS et al (July 2004). Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo. FASEB J 19 (9): 1166–1168.
  38. Smithells, D (November 1998). Does thalidomide cause second generation birth defects?. Drug Saf 19 (5): 339–341.
  39. Friedler, G (December 1996). Paternal exposures: impact on reproductive and developmental outcome. An overview.. Pharmacol Biochem Behav 55 (4): 691–700.
  40. Cicero, TJ, Adams NL, Giodarno A et al (March 1991). Influence of morphine exposure during adolescence on the sexual maturation of male rats and the development of their offspring. J Pharmacol Exp Ther. 256 (3): 1086–1093.
  41. Newbold, RR, Padilla-Banks E and Jefferson WN (June 2006). Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations. Endocrinology 147 (6 Suppl): S11–S17.
  42. Casadesus J and Low D (September 2006). Epigenetic Gene Regulation in the Bacterial World. Microbiol Mol Biol Rev 70 (3): 830-856.
  43. 43.0 43.1 Tost J (editor). (2008). Epigenetics, Caister Academic Press. ISBN 978-1-904455-23-3 .

External links

The development of phenotype
Developmental architecture: Segmentation | Modularity
Influential figures: C. H. Waddington | Richard Lewontin
Debates: Nature versus nurture
List of evolutionary biology topics

Around Wikia's network

Random Wiki