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In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- (Greek: επί- over, above, outer) -genetics. It refers to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such changes are DNA methylation and histone modification, both of which serve to regulate gene expression without altering the underlying DNA sequence. Conclusive evidence supporting epigenetics show that these mechanisms can enable the effects of parents' experiences to be passed down to subsequent generations.


One example of epigenetic changes in eukaryotic biology is the process of cellular differentiation. During morphogenesis, totipotent stem cells become the various pluripotent cell lines of the embryo, which in turn become fully differentiated cells. In other words, a single fertilized egg cell – the zygote – changes into the many cell types including neurons, muscle cells, epithelium, endothelium of blood vessels, etc. as it continues to divide. It does so by activating some genes while inhibiting others.[3]

In 2011, it was demonstrated that the methylation of mRNA has a critical role in human energy homeostasis. The obesity associated FTO gene is shown to be able to demethylate N6-methyladenosine in RNA. This opened the related field of RNA epigenetics.[4][5]

Etymology and definitionsEdit

File:Epigenetic mechanisms.jpg

Epigenetics (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the words genetics and epigenesis.[6] Epigenesis is an old[7] word that has more recently been used (see preformationism for historical background) to describe the differentiation of cells from their initial totipotent state in embryonic development. When Waddington coined the term the physical nature of genes and their role in heredity was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype.

Robin Holliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."[8] Thus epigenetic can be used to describe anything other than DNA sequence that influences the development of an organism.

The modern usage of the word in scientific discourse is more narrow, referring to heritable traits (over rounds of cell division and sometimes transgenerationally) that do not involve changes to the underlying DNA sequence.[9] 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 psychologist Erik Erikson used the term epigenetic in his book Identity: Youth and Crisis (1968). Erikson writes that the epigenetic principle is where "anything that grows has a ground plan, and that out of this ground plan, the parts arise, each part having its time of special ascendancy, until all parts have arisen to form a functioning whole."[10] That usage, however, is of primarily historical interest.[11]

Molecular basis of epigeneticsEdit

Epigenetic changes can modify the activation of certain genes, but not the sequence of DNA. Additionally, the chromatin proteins associated with DNA may be activated or silenced. This is why the differentiated cells in a multi-cellular organism express only the genes that are necessary for their own activity. Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic changes are inherited from one generation to the next.[12] This raises the question of whether or not epigenetic changes in an organism can alter the basic structure of its DNA (see Evolution, below), a form of Lamarckism.




Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:[13]

DNA methylation and chromatin remodelingEdit

Nucleosome 1KX5 2

DNA associates with histone proteins to form chromatin.










DNA methylation frequently occurs in repeated sequences, and helps to suppress the expression and mobility of 'transposable elements':[15] Because 5-methylcytosine can be spontaneously deaminated (replacing nitrogen by oxygen) 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.[16] DNMT1 is the most abundant methyltransferase in somatic cells,[17] localizes to replication foci,[18] has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).[19]

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.[20] DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.[16][21]





RNA transcripts and their encoded proteinsEdit



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.[31][32] 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 that results in suppression of nonsense mutations in other genes.[33] 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.[34][35]

Structural inheritance systemsEdit

For more details on this topic, see Structural inheritance.


Functions and consequencesEdit






Epigenetic mechanisms were a necessary part of the evolutionary origin of cell differentiation.[42] Although epigenetics in multicellular organisms is generally thought to be a mechanism involved in differentiation, with epigenetic patterns "reset" when organisms reproduce, there have been some observations of transgenerational epigenetic inheritance (e.g., the phenomenon of paramutation observed in maize). Although most of these multigenerational epigenetic traits are gradually lost over several generations, the possibility remains that multigenerational epigenetics could be another aspect to evolution and adaptation. A sequestered germ line or Weismann barrier is specific to animals, and epigenetic inheritance is expected to be far more common in plants and microbes. These effects may require enhancements to the standard conceptual framework of the modern evolutionary synthesis.[43][44]

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.[45] When the DNA sequence of the region is not mutated, this change is reversible. It has also been speculated that organisms may take advantage of differential mutation rates associated with epigenetic features to control the mutation rates of particular genes.[45] Interestingly, recent analyses have suggested that members of the APOBEC/AID family of cytosine deaminases are capable of simultaneously mediating genetic and epigenetic inheritance using similar molecular mechanisms.[46]




Epigenetic effects in humansEdit

Genomic imprinting and related disordersEdit

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.[51] The best-known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndrome—both can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.[52] 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 observationsEdit

See main article Transgenerational epigenetics

In the Överkalix study, Marcus Pembrey and colleagues observed that the paternal (but not maternal) grandsons[53] of Swedish men who were exposed during preadolescence to famine in the 19th century were less likely to die of cardiovascular disease. If food was plentiful, then diabetes mortality in the grandchildren increased, suggesting that this was a transgenerational epigenetic inheritance.[54] The opposite effect was observed for females—the paternal (but not maternal) granddaughters of women who experienced famine while in the womb (and therefore while their eggs were being formed) lived shorter lives on average.[55]

Twin studiesEdit

Recent studies involving both dizygotic and monozygotic twins have produced some evidence of epigenetic influence in humans.[56][57][58]

See also Edit

External linksEdit

References Edit

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  2. Special report: 'What genes remember' by Philip Hunter | Prospect Magazine May 2008 issue 146. URL accessed on 2012-07-26.
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  4. Jia, Guifang, Fu, Ye, Zhao, Xu, Dai, Qing, Zheng, Guanqun, Yang, Ying, Yi, Chengqi, Lindahl, Tomas, Pan, Tao, Yang, Yun-Gui, He, Chuan (16 October 2011). N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature Chemical Biology 7 (12): 885–887.
  5. New research links common RNA modification to obesity. URL accessed on 2012-07-26.
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  7. According to the Oxford English Dictionary:
    The word is used by W. Harvey, Exercitationes 1651, p. 148, and in the English Anatomical Exercitations 1653, p. 272. It is explained to mean ‘partium super-exorientium additamentum’, ‘the additament of parts budding one out of another’.
    It is also worth quoting this adumbration of the definition given there (viz., "The formation of an organic germ as a new product"):
    theory of epigenesis: the theory that the germ is brought into existence (by successive accretions), and not merely developed, in the process of reproduction. [...] The opposite theory was formerly known as the ‘theory of evolution’; to avoid the ambiguity of this name, it is now spoken of chiefly as the ‘theory of preformation’, sometimes as that of ‘encasement’ or ‘emboîtement’.
  8. Holliday R (November 1990). Mechanisms for the control of gene activity during development. Biol Rev Camb Philos Soc 65 (4): 431–71.
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  53. A person's paternal grandson is the son of a son of that person; a maternal grandson is the son of a daughter.
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  • R.A. Waterland, R.L. Jirtle, "Transposable elements: Targets for early nutritional effects on epigenetic gene regulation", Molecular and Cellular Biology 2003 August 1;23(15):5293-5300.
The development of phenotype
Developmental architecture: Segmentation | Modularity
Influential figures: C. H. Waddington | Richard Lewontin
Debates: Nature versus nurture
List of evolutionary biology topics

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